Antimicrobial compositions and uses thereof

ABSTRACT

In some aspects, provided herein are antimicrobial compositions comprising partially esterified polygalacturonic acid and certain fatty acids (e.g., caprylic acid). In some embodiments, the antimicrobial composition may be administered (e.g., topically or orally) to a subject, such as a human patient to treat an infection (e.g., an infection comprising a biofilm). In some aspects, improved catheters are provided.

This application is a divisional of U.S. application Ser. No.16/078,735, filed Aug. 22, 2018, which is a national phase applicationunder 35 U.S.C. § 371 of International Application No.PCT/US2017/018704, filed Feb. 21, 2017, which claims the benefit of U.S.Provisional Application Ser. No. 62/298,082, filed on Feb. 22, 2016, theentirety of each of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates generally to the field of molecularbiology and medicine. More particularly, it concerns antimicrobialcompositions.

2. Description of Related Art

The care and management of patients with chronic wounds especially thosewith cancer remain a major challenge for both the patient and theclinicians. Further complicating this situation is the paucity ofevidence-based treatment strategies for chronic wound care. An increasein the number of patients with chronic wound has been reported as aresult of an increase in the cancer patient population as well as thosewith advancing age. It has been estimated that approximately 1% of thepopulation will develop leg ulceration in the course of their lifetime.In the United States alone, chronic wounds affect 3 to 6 millionpatients annually with an estimated treatment cost of 5 to 10 billioneach year. Wounds can be difficult to heal due to the presence ofbiofilms particularly in immunocompromised cancer patients. This coupledwith the increasing emergence of antibiotic resistance-biofilm adverselyimpacts the outcomes of antibiotic wound therapies.

A review of the current practice advocate that systemically administeredantibiotics alone did not effectively decrease bacterial levels ingranulating wounds whereas topically applied antimicrobial can beeffective in improving patient outcome. Topical disinfection of skin andwounds, particularly microbially contaminated wounds, remains animportant healthcare need for preventing infections. Additionally,disinfection of medical devices, including indwelling ones, andimplantation sites (such as surgical sites) to prevent infectionsremains a significant healthcare need. Clearly, there is a need for newand improved antimicrobial compositions and methods of disinfectingsurfaces and treating infections.

SUMMARY OF THE INVENTION

In some aspects, the present invention overcomes limitations in theprior art by providing new and improved antimicrobial compositions. Thepresent invention is based, in part, of the discovery thatpolygalacturonic acid mixture such as partially esterifiedpolygalacturonic acid and a fatty acid (e.g., caprylic acid) cansynergistically function to enhance microbial compositions. Methods ofusing the antimicrobial compositions including, e.g., treating woundsand disinfecting surgical devices, skin, wounds, surgical sites, andsurfaces are also provided. In some embodiments, antimicrobialcompositions provided herein can be applied topically or to the skin orother tissue of a subject, such as a mammal or human to provide atherapeutic effect (e.g., cleaning a wound or surgical site,disinfection of microbes, promoting healing, and/or reducing pain).

In some aspects, provided herein are synergistic antimicrobialcompositions comprising partially esterified polygalacturonic acid(partially esterified PGA) and a fatty acid (e.g., a protonatedsaturated fatty acids such as caprylic acid) that can treat or eradicatebiofilms. In some embodiments, the concentrations of the partiallyesterified PGA and the fatty acid are sufficiently low such that littleor no associated toxicities are observed when the antimicrobialcomposition is administered to a human. In some embodiments, anenhancers such as a peroxide (e.g., hydrogen peroxide) and a nitricoxide donors (e.g., a glyceryl nitrate such as, for example glyceryltrinitrate) can be added to accelerate antimicrobial action. A chelator(e.g., EDTA, citrate, etc.) may be included in an antimicrobialcomposition as described herein, e.g., to improve antimicrobial activityand/or maintain desired local pHs. In addition, one or more thickener,gelling agent, emollient, surfactant, humectant, moisturizer,anti-inflammatory agent, coloring or tinting agents, and/or fragrancescan be added to an antimicrobial composition as described herein, e.g.,to improve handling properties for specific applications. In someembodiments, an antiseptic composition of the present invention may beused for (1) topical disinfection of skin and wounds, such asmicrobially contaminated wounds, as well as (2) disinfection of medicaldevices, including indwelling devices or implanted devices, and/or (3)disinfection of surgical sites. In some embodiments, the antimicrobialcomposition may comprise an antibiotic; nonetheless, in someembodiments, an antimicrobial composition of the present invention willdisplay disinfecting properties without the inclusion of an antibioticand it may be desirable to exclude antibiotics from the antimicrobialcomposition.

As shown in the below examples, in some aspects, antimicrobialcompositions comprising a partially esterified polygalacturonic acidmixture and capyrlic acid that are formulated for topical administrationare provided and may administered to a human patient (e.g., to treat awound). As shown in the examples, the antimicrobial composition may beformulated as a non-antibiotic, antimicrobial wound ointment that may beused, e.g., to clinically treat biofilm in the chronic wounds. It isanticipated that the antimicrobial ointment will accelerate woundhealing and may reduce the pain. Without wishing to be bound by anytheory, data presented in the examples supports the idea that inclusionof the partially esterified polygalacturonic acid may contribute to thesynergistic results with the fatty acid (e.g., caprylic acid) due tosome interaction with the caprylic acid that may involve, e.g.,improving the solubility of the fatty acid, providing emulsifyingproperties, and/or contributing to helping to maintain or buffer theacidic content of the antimicrobial composition.

An aspect of the present invention relates to an antimicrobialcomposition comprising: from about 0.5% to about 3% (w/w) of apolygalacturonic acid mixture and from greater than 0.1% to about 5%(w/w) of a C₆₋₁₂ fatty acid. The C₆₋₁₂ fatty acid may be a C₆₋₁₂saturated fatty acid or a C₆₋₁₂ alkanoic acid. The C₆₋₁₂ fatty acid maybe a C₆₋₁₀ saturated fatty acid or a C₆₋₁₀ alkanoic acid. The C₆₋₁₂fatty acid may be hexanoic acid, octanoic acid, decanoic acid,dodecanoic acid, caprylic acid (octanoic acid), caproic acid, or lauricacid. In some embodiments, the C₆₋₁₂ fatty acid is caprylic acid(octanoic acid). In some embodiments, the composition comprises fromabout 0.2% to about 5%, from about 0.3% to about 5%, from about 0.4% toabout 5%, or from about 0.4% to about 3% of the fatty acid. In someembodiments, the composition comprises from about 0.5%, 0.75%, 1%,1.25%, 1.5%, 1.75%, 2%, 2.5%, 3%, or any range derivable therein (e.g.,about 1%-3%), of the polygalacturonic acid. In some embodiments, thefatty acid is protonated or a free acid. The antimicrobial compositionmay have a pH of about 4.8 or less, about 3.7-4.8, or about 4-4.7. Insome embodiments, the ratio of the polygalacturonic acid mixtureconsists of esterified polygalacturonic acid and de-esterifiedpolygalacturonic acid in an amount of at least about 50% de-esterifiedpolygalacturonic acid. In some embodiments, said amount is at leastabout 70% de-esterified polygalacturonic acid, wherein the de-esterifiedpolygalacturonic acid is substantially deprotonated. In someembodiments, said amount is at least about 85% de-esterifiedpolygalacturonic acid, wherein the de-esterified polygalacturonic acidis substantially deprotonated. The antimicrobial composition may furthercomprise a peroxide. In some embodiments, the peroxide is hydrogenperoxide. The hydrogen peroxide may be present in the antimicrobialcomposition in an amount of from about 0.1% to about 3%, or from about0.1% to about 1%. The antimicrobial composition may further comprisesone or more additional antimicrobial agent. The one or more additionalantimicrobial agent may be an antibiotic, an antiseptic, chlorhexidine,gendine, gardine, silver, nanosilver, silver sulfadiazine,polyhexamethylene biguanide (PHMB), a chelator, a C₁₋₄ alcohol, a nitricoxide donor, a quarternary ammonium antimicrobial, or mixtures thereof.In some embodiments, the antimicrobial composition comprises the nitricoxide donor, and wherein the nitric oxide donor is a glyceryl nitrate,nitroprusside, nitrosoglutathione, a nitroso compound, nitrosothiol,nitrosocystein, nitrosoalbumin, nitro compounds, nitroaspiririn,isosorbide, diazeniumdiolate, nitrate, or nitrite. In some embodiments,the glyceryl nitrate is glyceryl trinitrate (GTN). In some embodiments,the antimicrobial composition comprises about 0.01-1% glyceryltrinitrate (GTN). The antibiotic is minocycline, rifampin, anaminoglycoside, quinolone, carbapenem, cephalosporin, glycopeptide,lipopeptide, lincosamide, macrolide, monobactam, nitrofuran,oxazolidinone, penicilin, polypeptide, sulfonamide, tetracycline,metronidazole, muciprocin, anti-mycobacterial compound, orchloramphenicol. In some embodiments, the C₁₋₄ alcohol is ethanol. Insome embodiments, the chelator is mercaptoethane sulfonate (MeSNA),citrate, EDTA, EDDS, or N-acetyl cysteine. In some embodiments, theantimicrobial composition further comprises an antibiotic; however, inother embodiments, the antimicrobial composition does not comprise anantibiotic. The antimicrobial composition may further comprise ananalgesic agent, an antiscarring agent, an anti-inflammatory agent, ananticoagulant, a fragrance, a moisturizer, glycerol, a siliconecompound, a vitamin, humectant, a polymer, a lubricant, a tactile agent,a thickener, a gelling agent, an emollient, a surfactant, an emulsifier,a moisturizer, a coloring or tinting agent, or a fragrance. The solutionmay comprise a pharmaceutically acceptable saline diluent. In someembodiments, the antimicrobial composition is further defined as apharmaceutical composition or comprises a pharmaceutically acceptableexcipient. The antimicrobial composition may comprise a protein such as,e.g., a gelatin, a plasticized gelatin (e.g., glycerol-gelatin), analginate, a chitosan, collagen, or a proteoglycan (e.g., hyaluronicacid). In some embodiments, the antimicrobial composition is formulatedfor topical administration or administration to a wound. Theantimicrobial composition may be formulated as an ointment, cream,spray, lotion, fluid, emulsion, suspension, microemusion, nanoemulsion,nanosuspension, or microsuspension. In some embodiments, theantimicrobial composition comprises a cellulose (e.g., carboxymethylcellulose) and a glycerol (e.g., propylene glycol). In some embodiments,the antimicrobial composition comprises about 1-5% carboxymethylcellulose and about 10-30% propylene glycol. In some embodiments, theantimicrobial composition comprises about 3% carboxymethyl cellulose andabout 20% propylene glycol. In some embodiments, the antimicrobialcomposition comprises about 0.5-2% pectinic acid, about 0.3-0.5%caprylic acid, and about 0.01-1% glyceryl trinitrate (GTN). In someembodiments, the antimicrobial composition comprises about 1% pectinicacid, about 0.4% Caprylic acid, and about 0.03% glyceryl trinitrate(GTN). In some embodiments, the antimicrobial composition comprisesabout 1-1000 micrograms/ml glyceryl trinitrate and about 0.1-1% hydrogenperoxide. In some embodiments, the antimicrobial composition is furtherdefined as a catheter lock or flush solution. In some embodiments, thecomposition comprises at least 0.75% or at least 1% of thepolygalacturonic acid.

Another aspect of the present invention relates to a syringe, comprisinga unit dose of a pharmacologically effective amount of an antimicrobialcomposition of the present invention or as described above.

Yet another aspect of the present invention relates to a vial,comprising a unit dose of a pharmacologically effective amount of anantimicrobial composition of the present invention or as describedabove.

Another aspect of the present invention relates to a medical devicelocking solution comprising or consisting of an antimicrobialcomposition of the present invention or as described above.

Yet another aspect of the present invention relates to a cathetercomprising an antimicrobial composition of the present invention or asdescribed above. The catheter may be a urinary catheter. In someembodiments, the urinary catheter is a double balloon catheter. In someembodiments, the urinary catheter is a Foley catheter, a double cuffedFoley catheter, or a Lerman Foley catheter.

Another aspect of the present invention relates to a method ofdisinfecting or cleaning a catheter in a subject, comprisingadministering an antimicrobial composition of the present invention oras described above to the catheter. The catheter may be an intravascularcatheter, a urinary catheter, a brain catheter, a soaker catheter, anephrostomy tube, or a drain or drainage catheter. In some embodiments,the catheter is a double balloon catheter, a single balloon catheter, aFoley catheter, or a Lerman Foley catheter. In some embodiments, thecatheter is a urinary catheter and the method further comprises byflushing the antimicrobial composition between the urethra and externalsurface of the catheter. In some embodiments, the catheter comprises aproximal reservoir, and wherein the method further comprises filling theproximal reservoir with the antimicrobial composition. In someembodiments, the antimicrobial composition can drain along the exteriorof the catheter shaft through one or more pores in the proximalreservoir. The proximal reservoir may be a cuff (e.g., an inflatablecuff). In some embodiments, the catheter comprises a distal reservoir.The distal reservoir may be a cuff (e.g., an inflatable cuff). In someembodiments, the method further comprises filling the distal reservoirwith the antimicrobial solution. In some embodiments, the antimicrobialcomposition can drain along the exterior of the catheter shaft throughone or more pores in the distal reservoir. In some embodiments, thecatheter comprises three or more reservoirs or cuffs. The subject may bea human or a non-human animal such as, e.g., a mammal, a dog, a cat, amouse, a primate, a monkey, an ape, a horse, a donkey, a pig, a sheep, agoat, or a cow. In some embodiments, the subject is a human.

Yet another aspect of the present invention relates to a composition foruse in flushing or locking a catheter in a subject, wherein thecomposition is an antimicrobial composition of the present invention oras described above, and wherein the antimicrobial composition is furtherdefined as a solution, an emulsion, or a suspension. The catheter may bean intravascular catheter, a urinary catheter, a brain catheter, anephrostomy tube, or a drain or drainage catheter. In some embodiments,the catheter is a double balloon catheter, a Foley catheter, or a LermanFoley catheter. In some embodiments, the subject is a human. In someembodiments, compositions and methods as described herein may be usedfor the treatment or disinfection of non-human animals, e.g., in aveterinary setting.

Another aspect of the present invention relates to a method of promotingwound healing or treating an infection in a subject, comprisingadministering an antimicrobial composition of the present invention oras described above to a wound or infection on or in the subject. In someembodiments, the antimicrobial composition is administered via acatheter, tube, canula, syringe, or soaker catheter. The antimicrobialcomposition may be formulated for topical administration. The subjectmay be a mammal such as, e.g., a dog, a cat, a mouse, a rat, a cow, adonkey, a pig, a sheep, or a horse. In some embodiments, the subject isa human.

Yet another aspect of the present invention relates to a composition foruse in promoting wound healing in a subject, wherein the composition isan antimicrobial composition of the present invention or as describedabove.

Another aspect of the present invention relates to a method of treatinga biofilm comprising contacting the biofilm with an antimicrobialcomposition of the present invention or as described above. The biofilmmay comprise or consists of gram-positive bacteria, gram-negativebacteria, or fungi.

The pH of the antimicrobial composition may be present at or adjusted toa pH (e.g., a pH of about 4.8 or less) so that the fatty acid (e.g., thecaprylic acid) is protonated or in a free acid state and/or thepolygalacturonic acid (PG) is in an ionized (deprotonated) state. Insome embodiments, the pH of the antimicrobial composition is about3.5-4.8, more preferably about 3.7-4.8, or 3.5, 3.6, 3.7, 3.8, 3.9, 4,4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0 or any range derivabletherein. In some embodiments, it is anticipated that it may be possibleto adjust the antimicrobial formulation to a lower pH range (e.g., pH2.0-3.5, pH 2.5-3.5) such that when the antimicrobial composition isapplied in vivo (e.g., to a lower pH environment such as the digestivetract). In certain cases the pH may shift in situ from the lower pHrange to a more alkaline pH range (e.g., pH 3.7-4.8). Generally,polygalacturonic acid (PG) has a pKa of about 3.7 (see Stoddart R W,Spires I P, Tipton K F., Biochem J. 1969 October; 114(4):863-70.Solution properties of polygalacturonic acid); thus, at a pH above 3.5the PG will be ionized (and not protonated). For example, in the pHrange 3.7-4.8 the caprylic acid will be protonated but the PG will notbe ionized (i.e., it will be deprotonated). Without wishing to be boundby any theory, the data provided herein supports the idea that when theantimicrobial composition comprises PG in an ionized (or deprotonated)state that this can help maintain the caprylic acid in the protonatedstate which may be necessary for its antimicrobial activity.

Polygalacturonic acid (e.g., a partially esterified polygalacturonicacid) in an antimicrobial composition as described herein may be ahomopolymer of galacturonic acid but can also be heteropolymers ofgalacturonic acid, Rhamnose and other neutral sugars (such as arabinose,galactose and xylose); however, the majority of monomeric units in apolygalgcturonic acid are galacturonic acid. Some of the galacturonicacid units can be esterified, most commonly methoxylated but can also beethoxylated (acylated), propoxylated and butoxylated etc. Some of thegalacturonic acid units are free acids or protonated. The degree ofesterification of partially esterified polygalacturonic acid can rangefrom about 0.01-99.99%, more preferably less than about 80%, and evenmore preferably less than about 50%.

Some aspects of the present invention relate to antimicrobialcompositions comprising a partially esterified polygalaturonic acid anda fatty acid. In some preferred embodiments, the fatty acid is aprotonated fatty acid or a free acid. In some embodiments, the fattyacid is caprylic acid. One or more enhancer such as a peroxide and/or anitric oxide donor (e.g., a glyceryl nitrate, glyceryl trinitrate (GTN))can be included in the antimicrobial composition, e.g., to improve thespeed of antimicrobial action. One or more chelators can also beincluded in the antimicrobial composition, e.g., to improveantimicrobial activity and/or maintain a desired local pH range. Thechelators may be, e.g., MeSNA, a citrate, an EDTA, and/or an EDDS. Inaddition, thickeners, gelling agents, emollients, surfactants,emulsifiers, humectants, moisturizers, coloring or tinting agents andfragrances can be added to compositions of this invention to improvehandling properties for specific applications.

Antimicrobial compositions as described herein may be used for a varietyof purposes including, e.g., treatment of chronic wounds. For example,partially esterified polygalacturonic acid and fatty acids may be addedto one or more thickening agents such as, e.g., methylcelluloses,hydroxymethylcelluloses, hydroxypropylmethylcelluloses and/orcarboxymethylcelluloses which may help retain the composition in a woundand/or help absorb exudate. An ointment may further include a humectantsuch as propylene glycol. Without wishing to be bound by any theory, thehumectant may facilitate contact with microbial biofilm present in woundbeds and may help preserve a moist environment conducive to woundhealing. The antimicrobial composition may further comprise an enhancersuch as a nitric oxide donor and/or a peroxide, e.g., to acceleratebiofilm eradication. In some embodiments, the antimicrobial compositionfurther comprises one or more nitroprussides, nitrosoglutathiones, othernitroso compounds, nitrosothiols, nitrosocystein, nitrosoalbumin, nitrocompounds, nitroaspiririns, isosorbides, diazeniumdiolates, nitrates andnitrites, a glyceryl nitrate, such as glyceryl trinitrate, and/or dilutehydrogen peroxide (e.g., less than about 1%, or 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9% or any range derivable therein).

A variety of additional components may be included in an antimicrobialcomposition as described herein. For example, when it is desired to usethe antimicrobial composition for skin disinfection, thepolygalacturonic acid mixture and the fatty acid (e.g., caprylic acid)may be suspended in a volatile vehicle such as, e.g., water, an alcohol(e.g., ethanol, isopropyl alcohol), or a silicone which may allowapplication to skin but later evaporate, leaving antimicrobialcomponents (e.g., the polygalacturonic acid mixture and the fatty acid)as a residue. In some embodiments, one or more emolients and/orsurfactants may be included to improve tactile feel as can coloring ortinting agents. In some embodiments, the antimicrobial composition maybe formulated as a low viscosity composition that can be sprayed (e.g.,for application to skin or other surfaces). In some embodiments theantimicrobial composition can be delivered through an irrigationcatheter, a soaker catheter, a cannula, a tube, a needle, or a trocar(e.g., to a surgical or other site with limited access). In someembodiments the antimicrobial composition can be formulated as asuppository, a hydrocolloid, particles, an emulsion, a suspension, acream, or a paste. In some embodiments, the antimicrobial compositionmay be used for cleaning or disinfection of an indwelling or prostheticmedical device. These devices include catheters, tubes, stents, drains,dressings, shunts, pins etc. In some embodiments, the medical device isa urinary catheter such as a Foley catheters. Foley catheters typicallyconsist of an open lumen through which urine can void and one or moreinflatable cuffs. In some cases an inflatable cuff is present near thedistal tip which resides distal to the urethral sphincter and wheninflated retains the distal tip in the bladder. Inflation of cuffs istypically controlled by small lumens residing in the catheter wall.Foley catheters can frequently indwell for prolonged durations of longerthan several days which increases the likelihood of microbialcolonization and urinary tract infections. Antimicrobial compositions ofthe present invention may be instilled through the lumen into a drainingcuff or reservoir from where they can drain along the shaft of thecatheter in contact with the urethra. Thickeners and wetting agents suchas, e.g., carboxymethylcellulose and/or propylene glycol may be includedin the antimicrobial composition to control the rate of drainage andprolong contact times of the partially esterified polygalacturonic acidand fatty acids with the catheter. These approaches may be used, e.g.,for treating, disinfecting, or eradicating a biofilm on the catheter ormedical device. In another embodiment the medical device is a soakercatheter where antimicrobial compositions of the present invention canbe instilled through the lumen and drain through the wall of thecatheter to the external surfaces or contacting tissues. In yet anotherembodiment the medical device is a drainage tube where the antimicrobialcompositions of the present invention can be instilled through a lumensand be conveyed to drain along the external surfaces through soakerpores or draining reservoirs.

Antimicrobial compositions as described herein may be pre-added to solidsponges or hydrogel matrices (e.g., for application or retention onsurfaces such as skin or a medical device, catheter or prosthetic). Theantimicrobial composition may comprise one or more of polyvinyl alcohol,hydrophilic polyurethanes, gelatin, collagen, chitosans, pectins,alginates and/or celluloses. Hydrogels may have higher affinity to waterthan other solvents (e.g., such as glycols) but may initially be loadedwith a lower-affinity solvent which will be slowly displaced as water isabsorbed. Hydrogel systems comprising a hydrogel matrix may be usedrelease antimicrobial components from an antimicrobial composition ofthe present invention in the non-aqueous solvent as water is absorbedfrom the environment into the hydrogel matrix.

The duration of contact needed for disinfecting surfaces by fluidcontact can vary by organism and/or by how well established a biofilm isbeing treated. As shown in the below examples, the inventors have foundthat biofilms can be eradicated within 2 hours by contact withcompositions of low enough toxicity that they are suitable for use inintravascular devices.

Other physiologic surfaces which could be treated with the compositionsdisclosed here include, e.g., skin and wound beds, teeth, the oro andnasopharynx, surgical sites, organs, nerve tissue, tendons, cartilageand bone. In some embodiments, a solution of the present invention maybe sprayed, nebulized, or inhaled by a subject into a lung, sinus, orrespiratory tissue to treat or clean a wound or tissue, or reduce thegrowth of bacteria or fungi on the tissue. In some embodiments, asolution of the present invention may be administered topically to asubject, such as a human patient, to treat or prevent a sexuallytransmitted disease (STD). For contact with physiologic surfaces anantimicrobial composition of the present invention may be formulatedinto a gel, cream, or film, and the composition may include one or morecoloring, aromatic, lubricious, moisturizing, pain relief and/oranti-inflammatory additive. Implanted medical device surfaces to whichthese compositions can be applied include, but are not limited to,catheters, cords, tubes, drains, shunts, stents, sutures, clips,staples, dressings, meshes, casings, etc. Environmentally exposedsurfaces of plants, devices, buildings or machines can be treated withthese compositions including surfaces in showers, locker-rooms,bathrooms and medical facilities. Surfaces of personal care and/orprotection articles such as gloves, masks, respirators, patches, footcovers, shoe liners, flip flops, ear plugs, nose plugs etc. may besubstantially disinfected with these compositions.

The antimicrobial compositions of the present invention may be contactedwith a surface for a variety of periods of time to kill microorganismsor reduce the growth of microorganisms. For example, the contacting maybe performed for at least 1, 2, 3, 4, 5 hours or at least 1, 2, 3, 4, 5or more days, or 1, 2, 3, 4, 5 or more weeks, etc. In some embodiments,the contacting may be performed for less than 5, 4, 3, 2, or 1 hours, orless than 45, 30, or 15 minutes.

In addition to antimicrobial agents, an analgesic agent (e.g.,lidocaine), an antiscarring agents (e.g., MeSNA), an anti-inflammatoryagent (e.g., a steroid, a TNF alpha inhibitor, an aspirin, an ibuprofen,a cyclo-oxygenase inhibitor, a naproxen a non-steroidalanti-inflammatory agent), an anesthetic (e.g., a local anesthetic), or apain-killer. In some embodiments, the antimicrobial compositioncomprises a leukotriene inhibitor such as, e.g., acitazanolast,iralukast, montelukast, pranlukast, verlukast, zafirlukast, andzileuton.

In some embodiments, an antimicrobial composition of the presentinvention does not contain an antibiotic. Nonetheless, in someembodiments, it may be desirable to include an antibiotic in anantimicrobial composition of the present invention. For example, anantimicrobial composition of the present invention may include member ofthe tetracycline group of antibiotics such as tigecycline, minocycline,doxycycline, or demeclocycline and/or analogs such asanhydrotetracycline, chlorotetracycline, or epioxytetracycline. In someembodiments, it is anticipated that a derivative of minocycline may besubstituted for minocycline in various antimicrobial solutions orcatheter lock solutions as described herein. In some embodiments,antimicrobial solutions or catheter lock solutions as described hereinmay include one or more additional antiviral agents and/or antifungalagents.

The antimicrobial composition may further comprises an antiseptic agent.Several antiseptic agents are known in the art and these include ataurinamide derivative, a phenol, a quaternary ammonium surfactant, achlorine-containing agent, a quinaldinium, a lactone, a dye, athiosemicarbazone, a quinone, a carbamate, urea, salicylamide,carbanilide, a guanide, an amidine, an imidazoline biocide, acetic acid,benzoic acid, sorbic acid, propionic acid, boric acid, dehydroaceticacid, sulfurous acid, vanillic acid, esters of p-hydroxybenzoic acid,isopropanol, propylene glycol, benzyl alcohol, chlorobutanol,phenylethyl alcohol, 2-bromo-2-nitropropan-1,3-diol, formaldehyde,glutaraldehyde, calcium hypochlorite, potassium hypochlorite, sodiumhypochlorite, iodine (in various solvents), povidone-iodine,hexamethylenetetramine, noxythiolin, 1-(3-choroallyl)-3,5,7-triazo1-azoniaadamantane chloride, taurolidine, taurultam, N(5-nitro-2-furfurylidene)-1-amino-hydantoin, 5-nitro-2-furaldehydesemicarbazone, 3,4,4′-trichlorocarbanilide,3,4′,5-tribromosalicylanilide,3-trifluoromethyl-4,4′-dichlorocarbanilide, 8-hydroxyquinoline,1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecar-boxylicacid,1,4-dihydro-1-ethyl-6-fluoro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxyli-cacid, hydrogen peroxide, peracetic acid, phenol, sodium oxychlorosene,parachlorometaxylenol, 2,4,4′-trichloro-2′-hydroxydiphenol, thymol,chlorhexidine, benzalkonium chloride, cetylpyridinium chloride, silversulfadiazine, or silver nitrate.

In some embodiments, the antimicrobial composition or composition maycomprise a basic reagent and/or a dye. The basic reagent may be aguanidium compound, a biguanide, a bipyridine, a phenoxide antiseptic,an alkyl oxide, an aryl oxide, a thiol, a halide, an aliphatic amine, oran aromatic amine. In some specific aspects, the basic reagent is aguanidium compound. Non-limiting examples of guanidium compounds includechlorhexidine, alexidine, hexamidine, and polyhexamethylene biguanide(PHMB). In other specific embodiments, the basic reagent is abipyridine. One example of a bipyridine is octenidine. In yet otheraspects, the basic reagent is a phenoxide antiseptic.

The dye may be a triarylmethane dye, a monoazo dye, a diazo dye, anindigoid dye, a xanthene dye, an anthraquinone dye, a quinoline dye, anFD&C dye. Non-limiting examples of triarylmethane dye include gentianviolet, crystal violet, ethyl violet, or brilliant green. Exemplarymonoazo dyes inlude FD&C Yellow No. 5, or FD&C Yellow No. 6. Othernon-limiting examples of FD&C dye include Blue No. 1 or Green No. 3. Onenon-limiting example of diazo dyes is D&C Red No. 17. An example of anindigoid dye is FD&C Blue No. 2. An example of a xanthene dye is FD&CRed No. 3; of an anthraquinone dye is D&C Green No. 6; and of anquinoline dye is D&C Yellow No. 1.

In some embodiments, an antimicrobial may contain one or moreantiseptics. For examples, the antiseptic may be a phenoxide antiseptic(e.g., clofoctol, chloroxylenol or triclosan), gendine, genlenol,genlosan, or genfoctol.

Antimicrobial compositions and methods described herein can be used toreduce microbial agents (e.g., bacteria) from the surface of a medicaldevice such as, e.g., a catheter, a drain, an endotracheal tube, anephrostomy tube, a ventricular catheter or shunt, a biliary stent, anorthopedic device, a prosthetic valve, a medical implant, dental devicesor dental implants, cardiac assist devices, vascular grafts,tracheostomy, ventriclulostomy devices, or intrathecal devices. In someaspects, the catheter is an indwelling catheter such as a central venouscatheter, a peripheral intravenous catheter, an arterial catheter, aSwan-Ganz catheter, a hemodialysis catheter, an urinary catheter (e.g.,a Foley catheter, a Lerman Foley catheter), a peritoneal catheter, anumbilical catheter, a percutaneous nontunneled silicone catheter, acuffed tunneled central venous catheter or a subcutaneous central venousport. In some embodiments, the medical device is an endotracheal tube, avascular catheter, a urinary catheter, a nephrostomy tube, a biliarystent, a peritoneal catheter, an epidural catheter, a central nervoussystem catheter, an intracranial catheter, an intraspinal catheter, anepidural catheter, an orthopedic device, a prosthetic valve, or amedical implant. The catheter may be a vascular catheter such as, e.g.,a central venous catheter, an arterial line, a pulmonary arterycatheter, and a peripheral venous catheter, an intraarterial catheter,or intravenous (i.v.) tubing.

In some embodiments, a pharmaceutical composition or catheter locksolution of the present invention may comprise a pharmaceuticallyacceptable excipient. The phrases “pharmaceutically acceptable” and“pharmacologically acceptable” refer to molecular entities andcompositions that do not produce an adverse, allergic or other untowardreaction when administered to an animal, such as, for example, a human,as appropriate. The preparation of an pharmaceutical composition thatcontains an antimicrobial composition (e.g., a catheter lock solution,an ointment, a gel, a spray, a composition formulated for topicaladministration or administration to the skin or a wound, etc.) of thepresent invention and an additional active ingredient will be known tothose of skill in the art in light of the present disclosure, asexemplified by Remington: The Science and Practice of Pharmacy, 21^(st)Ed., Lippincott Williams and Wilkins, 2005, incorporated herein byreference. Moreover, for animal (e.g., human) administration, it will beunderstood that preparations should typically meet sterility,pyrogenicity, general safety and purity standards as required by FDAOffice of Biological Standards. In some embodiments, the antimicrobialcomposition may comprise one or more ingredient as described in U.S.Pat. Nos. 7,601,731, 5,362,754 and 5,688,516, which are incorporated byreference in their entirety without disclaimer. In some embodiments, anantimicrobial composition or catheter lock solution of the presentinvention may comprise one or more additional antiviral or antifungalagent.

Particular embodiments include a kit comprising an antimicrobialcomposition as disclosed herein, (including for example any one ofclaims 1-48), an absorbent element, a swab, an adhesive dressing, and adisposal bag; optionally, the kit may comprise a pair of gloves (e.g.,sterile nitrile or latex gloves). In some embodiments, the kit is a careand maintenance kit for urinary (or other indwelling catheters) where adisinfecting liquid is packaged in a unit dose container forinstillation (e.g. one or more syringes) and is combined with anabsorbent element (such as a sponge or gauze described herein) in thekit to absorb any excess liquid that discharges at the proximal exitsite of the device. In the case of a topical or wound ointment, the kitmay include a wipe to clean the site, a swab or brush to spread theointment, and an adhesive dressing to cover the site. In specificembodiments, the kit can also contain a disposal bag or container(including one suitable and marked for biohazardous disposal).

Certain embodiments include a catheter comprising: a first end and asecond end; a central lumen extending from the first end and the secondend; a catheter wall disposed around the central lumen, wherein thecatheter wall comprises an outer surface; a first reservoir and a secondreservoir; a first conduit in fluid communication with the firstreservoir; a second conduit in fluid communication with the secondreservoir; and a plurality of outlet ports in in the first reservoir.

Particular embodiments further comprise a first inlet port in fluidcommunication with the first conduit, and a second inlet port in fluidcommunication with the second conduit. In some embodiments the firstconduit and the second conduit are in located within the catheter wall.In specific embodiments the plurality of outlet ports are arrangedcircumferentially around the outer surface of the catheter wall. Certainembodiments further comprise a first valve configured to control flow inthe first conduit, and particular embodiments further comprise a secondvalve configured to control flow in the second conduit. Some embodimentsfurther comprise an irrigation fluid container in fluid communicationwith the first conduit. In specific embodiments the irrigation fluidcontainer is a first syringe, and in certain embodiments the irrigationfluid container is coupled to a pump.

In particular embodiments the irrigation fluid container comprises anantimicrobial composition as disclosed herein (including for example,any one of claims 1-48). In some embodiments the irrigation fluidcontainer is configured to direct irrigation fluid through the firstconduit and the plurality of outlet ports in the first reservoir.Specific embodiments further comprise a first inlet port in fluidcommunication with the first conduit, where the first inlet port isproximal to the first end. Certain embodiments further comprise anirrigation fluid container configured to direct irrigation fluid throughthe first inlet port, the first conduit and the plurality of outletports in the first reservoir.

Particular embodiments further comprise a pressure source in fluidcommunication with the second conduit, and in some embodiments thepressure source is a second syringe. In specific embodiments thepressure source is configured to inflate the second reservoir via thesecond conduit. Certain embodiments further comprise a second inlet portin fluid communication with the second conduit, wherein the second inletport is proximal to the second end. In some embodiments the pressuresource is configured to inflate the second reservoir via the secondinlet port and the second conduit.

Other than reduction/eradication of microbes in medical devices, theflush solutions of the present invention are also useful in theeradication of the surfaces of other surfaces that microbes can grow onsuch as pipes, pipelines (e.g., an oil or water pipeline), ice machines,etc. In some embodiments, an antimicrobial composition of the presentinvention may be used for oral hygiene, e.g., as a mouthwash or fortopical (skin) disinfection. In some embodiments, an antimicrobialcomposition of the present invention may be used with or included in oron a bandage, dressing (e.g., wound dressing), cast, suture, or staple.In some embodiments, an antimicrobial composition as described hereinmay be used to clean or disinfect a surface, or may be included on asponge, gauze, a towel, or a wipe.

An “antimicrobial agent” is defined herein as an agent that hasantibiotic properties against bacteria, fungi, viruses and otherpathogens and includes antibacterial agents, antifungal agents,antiviral agents and antiseptic agents.

As used herein, the term “antifungal agent” is defined as a compoundhaving either a fungicidal or fungistatic effect upon fungi contacted bythe compound. As used herein, the term “fungicidal” is defined to meanhaving a destructive killing action upon fungi. As used herein, the term“fungistatic” is defined to mean having an inhibiting action upon thegrowth of fungi.

As used herein, the term “antibacterial agent” is defined as a compoundhaving either a bactericidal or bacteriostatic effect upon bacteriacontacted by the compound. As used herein, the term “bactericidal” isdefined to mean having a destructive killing action upon bacteria. Asused herein, the term “bacteriostatic” is defined to mean having aninhibiting action upon the growth of bacteria.

As used herein, the term “antiviral agent” is defined as a compound thatcan either kill viral agents or one that stops the replication ofviruses upon contact by the compound.

For the purposes of this disclosure, the phrase “effective amount” or“therapeutically effective amount” is defined as a dosage sufficient toinduce a microbicidal or microbistatic effect upon the microbescontacted by the composition on a surface.

As used herein the terms “contact”, “contacted”, and “contacting”, or“exposed” and “exposure” are used to describe the process by which anyof the antimicrobial compositions disclosed in the present invention,comes in contact with or direct juxtaposition with a surface of amedical device or any other surface from which microbial growth is to bereduced or eradicated.

As used herein in the specification, “a” or “an” may mean one or more.As used herein in the claim(s), when used in conjunction with the word“comprising”, the words “a” or “an” may mean one or more than one. Asused herein “another” may mean at least a second or more.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.” As used herein “another”may mean at least a second or more.

Throughout this application, the term “about” is used to indicate that avalue includes the inherent variation of error for the device, themethod being employed to determine the value, or the variation thatexists among the study subjects.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIGS. 1A-C: Synergy of Polygalacturonic Acid and Caprylic Acid testedagainst MRSA (FIG. 1A), MDR-Ps. aerugoinosa (FIG. 1B), Candida albicans(FIG. 1C)

FIGS. 2A-C: Synergy of Polygalacturonic Acid and Caprylic Acid testedagainst MRSA (FIG. 2A), Pseudomonas aerugoinosa (FIG. 2B), Candidaalbicans (FIG. 2C) using the modified Kuhn's model, quantitativetime-to-kill biofilm eradication model.

FIG. 3: In vitro cytotoxicity metabolic activity assay results.

FIG. 4: In vitro cytotoxicity assay results using mammalian fibroblastmodel.

FIG. 5: A schematic drawing of a catheter according to exemplaryembodiments of the present disclosure.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention overcomes limitations in the prior art byproviding improved antimicrobial compositions. In some aspects, thepresent invention is based, in part, on the observation that partiallyesterified polygalacturonic acid and caprylic acid can synergisticallyresult in improved bacterial killing and antimicrobial properties. Asshown in the below examples, partially esterified polygalacturonic acidor caprylic acid display very weak antimicrobial activity whenadministered alone; however, a synergistic and very strong antimicrobialactivity was observed when these compounds are administered together.The antimicrobial compositions may be used in methods including, e.g.,cleaning or disinfecting a medical device (e.g., a catheter), aprosthetic, a surface, skin, wound (e.g., as a lavage), or a surgicalsite.

In some embodiments, compositions of the present invention may betopically applied to the skin of a subject (e.g., a human patient) totreat an infection, e.g., that comprises a biofilm. Wounds in microbialcontaminated environments can be difficult to heal due to the presenceof biofilms. Biofilms are frequently present in chronic dermal woundsand contribute to their recalcitrance in healing (James et al., 2008).Staphylococcal biofilms have been reported to impair healing by delayingre-epithelialization of dermal wounds (Schierle et al., 2009). Theincreasing prevalence of antibiotic-resistant biofilms (US Department ofHealth and Human Services CfDCaP. Antibitoic Resistance Threats in theUnited States, 2013), impairs the efficacy of antibiotic woundtherapies. We have developed a novel, non-antibiotic, antimicrobialwound ointment that is comprised of a combination of agents known to besafe if used topically on the skin. In vitro testing has shown theointment to be highly effective in rapidly eradicating resistant grampositive, gram negative and fungal pathogens.

I. DEFINITIONS

The terms “antimicrobial medical device” and “medical device” as usedherein, refer to an instrument, apparatus, implement, machine,contrivance, implant, or other similar or related article, including acomponent part, or accessory, which is subjected to sequentialantimicrobial contact as described, and is intended for use in thediagnosis, treatment, and/or prevention of disease or otherhealth-related condition in a subject. The subject can be anyvertebrate, such as a mammal or a human. Non-limiting examples ofantimicrobial medical devices include vascular catheters, such asperipherally insertable central venous catheters, dialysis catheters,long term tunneled central venous catheters, peripheral venouscatheters, single-lumen and multiple-lumen short-term central venouscatheters, arterial catheters, pulmonary artery Swan-Ganz catheters, andthe like; urinary catheters, other long term urinary devices, tissuebonding urinary devices, renal stents, penile prostheses, vasculargrafts, vascular access ports, wound drain tubes, hydrocephalus shunts,ventricular drainage catheters, neurologic and epidural catheters,neurostimulators, peritoneal dialysis catheters, pacemaker capsules,artificial urinary sphincters, small or temporary joint replacements,dilators, heart valves, orthopedic prosthesis, spinal hardware, surgicalsite repair mesh (e.g., hernia mesh), endotracheal tubes, biliarystents, gastrointestinal tubes, gloves (including latex, non-latex andnitrile), other medical garb, charts, bed rails, condoms, colorectaltract implants, male and female reproductive implants, cosmetic orreconstructive implants (e.g., breast, chin, cheek, buttock, nasal),medical device envelopes and pouches, including stethoscope drums,orthopedic implants (e.g., joint (knee, hip, elbow, shoulder, ankle),prostheses, external fixation pins, intramedullary rods and nails, spineimplants), other medical and indwelling devices that may be subject tomicrobial infestation and/or activity; and metallic devices, such ascardiac pacemakers, defibrillators, electronic device leads, adaptors,lead extensions, implantable infusion devices, implantable pulsegenerators, implantable physiological monitoring devices, devices forlocating an implantable pulse generator or implantable infusion deviceunder the skin, and devices (e.g. refill needles and port accesscannulae) for refilling an implantable infusion device. In someembodiments, antimicrobial compositions or solutions of the presentinvention may be used to substantially disinfect or reduce the growth ofa microorganism (e.g., a bacteria of fungi) on a lumenal surface of avascular catheter; for example the antimicrobial composition or solutionmay be used to flush the catheter and/or as a locking solution.

The term “antimicrobial agent”, as used herein, refers to an agent, suchas an antibiotic or an antiseptic, capable of preventing or reducing thegrowth or reproduction of a microorganism, such as a bacterial or fungalmicroorganism, or of killing a microorganism.

The term “bacterial and fungal organisms” as used in the presentinvention means all genuses and species of bacteria and fungi, includingbut not limited to all spherical, rod-shaped, and spiral bacteria.Non-limiting examples of bacteria include staphylococci (e.g.,Staphylococcus epidermidis, Staphylococcus aureus), Enterrococcusfaecalis, Pseudomonas aeruginosa, Escherichia coli, among othergram-positive bacteria and gram-negative bacilli. Non-limiting examplesof fungal organisms include Candida albicans and Candida krusei.

II. ANTIMICROBIAL COMPOSITIONS

In some aspects, the present disclosure provides compositions comprisingpolygalacturonic acid and caprylic acid. The composition (e.g., aaqueous composition, an ointment, etc.) may have an acidic pH such as,e.g., a pH of less than about 5. In some embodiments, the pH of thecomposition is from about 2 to about 5. In some embodiments, the pH islower than 5. In some embodiments, the pH of the composition is fromabout 4 to about 4.5. In some embodiments, the composition is formulatedin a buffer, such as an aqueous buffer. In some embodiments, thecomposition is formulated in a saline solution. The aqueous solution maybe an isotonic 0.9% w/v saline solution. Other non-limiting examples ofsaline solutions which may be used are about 0.18%, 0.22%, 0.45%, 0.65%,3%, 5%, 7%, or about 23.4% saline concentration. In some embodiments,the aqueous composition comprises a saline solution or a buffer solutionwhich has been sterilized.

In some aspects, improved antimicrobial compositions that may beformulated as a wound ointment and include polygalacturonic acid andcaprylic acid, optionally further comprising a nitric oxide donor (e.g.,glyceryl trinitrate). As shown in the below examples, these compositionscan display in vitro antimicrobial synergies, and these activeingredients are considered to be environmentally friendly green agentsthat are well known to have low toxicities towards humans. Previouslythe inventors have shown that the combination of glyceryl trinitrate(nitroglycerin), and the medium chain fatty acid, caprylic acid, canrapidly (within 2 hrs) eradicate biofilms of significant gram positive,gram negative and fungal biofilms (Rosenblatt et al., 2015). Withoutwishing to be bound by any theory, nitric oxide (donated bynitroglycerin) may accelerate wound healing by promoting angiogenesis,fibroblast migration and collagen deposition (Han et al., 2012).Nitroglycerin is widely used for treating hypertension in much higherdoses than doses listed herein for wound treatment, and nitroglycerinmay be administered through the skin (transdermally). Medium chain fattyacids (including caprylic acid) have been used in treating wounds inSouth America (Pieper and Caliri 2003). They are components included inskin creams and total parenteral nutrition formulations, and have beenapproved by FDA with GRAS (Generally Recognized as Safe) status.Glyceryl trinitrate (GTN) may be used in treating chronic infectedgastrointestinal (GI) wounds. Wounds in the GI tract are complex to healbecause these areas naturally contain high contents of microbial florawhich can readily contaminate epithelial lesions. In 2011, the FDAapproved Rectiv™ ointment (Actavis, Parsippany, N.J.) which contains0.4% GTN in a petrolatum base. Clinical trials showed that GTN ointmentled to more rapid healing and reduced pain (Karanlik et al., 2009 andFenton et al., 2006). The primary side effect was transient dose-relatedheadache. Nitroglycerin-caprylic acid combination compositions presentedin the below Examples reduces the GTN dose to less than 1/10^(th) ofthat in Rectiv™ ointment, and it is anticipated by the inventors thatthese reduced dosages presented herein may therefore significantlyreduce or eliminate these dose-related side effects.

As shown herein and in the below Examples, the inventors have found thatthe combination of caprylic acid (CAP) and pectinic acid (PG) candisplay highly synergistic results in rapidly eradicating biofilm.Pectinic acid (also pectic or polygalacturonic acid) is naturallyderived from fruit pectin, and is widely used in topical creams andother skin applications. It has been formally designated by FDA as GRAS[21CFR184.1588. Apr. 1, 2014] and can help maintain an acidic pH (4-4.5)in wound beds which is beneficial to wound healing.

A. Partially Esterified Polygalacturonic Acid

In some aspects, the present disclosure provides composition comprisinga polygalacturonic acid (PG). Generally, esterified polygalacturonicacids have esterified carboxylic acid groups (e.g., esterified with analkyl_((C1-6)) or a cycloalkyl_((C3-6)) group), and de-esterifiedpolygalacturonic acids have carboxylic acids that are either in adeprotonated or protonated form. In some preferred embodiments, theantimicrobial composition comprises a partially esterifiedpolygalacturonic acid in its ionized or deprotonated form.

Polygalacturonic acid (PG) can be naturally derived from pectin which isa structural biopolymer (polysaccharide) present in the cell walls offruits and vegetables. Naturally derived PG is partially esterified(usually methoxylated), is usually derived from citrus rind or applepomace and may contain minor components of other sugar molecules in itsbackbone (Sriamornsak 2013). The pK of PG varies with degree ofesterification but ranges from about 3.5 to 4.1. At pHs above the pK, PGis usually soluble; however, at pHs below its pK it can form gels. Themolecular weight of naturally derived PG is typically between 50 and 150KDa (Sriamornsak 2013). PG is widely used in foods and is used inpharmaceutical tableting, coatings, in topical skin care products as acomplex with Allantoin (Becker et al., 2010) as well as in wound healingproducts (Munarin et al., 2012). PG has been deemed GenerallyRecocognized as Safe (GRAS) by the FDA (Adminstration USFaD. Part 184,Section 1588, Pectins. In: Adminstration USFaD, ed. Code of FederalRegulations Title 21; 2015).

In some embodiments, the polygalacturonic acid (e.g., a de-esterifiedPGA or a partially esterified PGA) is a polymer further defined by thestructure:

wherein: R₁ is hydrogen, alkyl_((C1-6)), substituted alkyl_((C1-6)),cycloalkyl_((C3-6)), or substituted cycloalkyl_((C3-6)). Thepolygalacturonic acids that may be used in the composition describedherein may have a polymeric length of 3 to 1000 repeating units (n). Insome embodiments, the number of repeating unit is from 10-750, 50-750,50-500, of 100-500 repeating units. In some embodiments, a combinationof polygalacturonic acids having a variety of polymer lengths (e.g.,ranging from 3 to 1000 repeating units) may be included in anantimicrobial composition as described herein. In various embodiments, apolygalacturonic acid may be processed to produce increasing amounts ofde-esterified polygalacturonic acid. The length of the polygalacturonicacid may be from about 50 to about 750 repeating units or from about 100to about 500 repeating units. In some embodiments, the composition maycomprise a polygalacturonic acid that is esterified at R₁ with analkyl_((C1-6)) or substituted alkyl_((C1-6)); in some preferredembodiments, the composition comprises a ratio of (de-esterifiedpolygalacturonic acid/esterified polygalacturonic acid) % of at least50, 55, 60, 65, 70, 75, 80, 85, or 90 percent or higher or any rangederivable therein of de-esterified polygalacturonic acid. In someembodiments, alkyl group at R₁ is methyl, ethyl, propyl, isopropyl, orbutyl. In some aspects, the present disclosure provides polygalacturonicacid which has been esterified at some percentage of the R₁ positions;for example at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 85, or 90 percent or higher or any range derivable therein ofthese groups are in the de-esterified or protonated form, and theremaining carboxylic acid groups are esterified (e.g., esterified asmethyl esters). In some embodiments, the percentage of the esterifiedcarboxylic acid is from about 0.1% to about 75%, from 0.5% to about 50%,from about 0.5% to about 25%, or from about 1% to about 15%.

As used herein, the term “de-esterified polygalacturonic acid” refers toa polygalacturonic acid that has a carboxylic acid that is in aprotonated or free acid form.

As used herein the term “partially esterified polygalacturonic acid” ora “polygalacturonic acid mixture” refers to a combination of bothesterified polygalacturonic acid and de-esterified polygalacturonicacid. For example, the amount of de-esterified PGA may be at least 50,55, 60, 65, 70, 75, 80, 85, 90, 95% or greater, or any range derivabletherein.

In some aspects, the compositions of the present disclosure comprisesfrom 0.5% to 10% of the polygalacturonic acid mixture (e.g., partiallyesterified polygalacturonic acid). The compositions may comprise from0.5% to 5%, from 0.5% to 3%, from 0.5% to 2%, or about 1% of thepolygalacturonic acid. In some embodiments, the composition comprisesfrom about 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.5%, 3%,3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9% to about 10%, or any range derivabletherein. In some preferred embodiments, the polygalacturonic acid (e.g.,partially esterified polygalacturonic acid) is in an ionic ordeprotonated state.

B. Medium Chain Fatty Acids and Monoglycerides

Previously, the inventors have observed antimicrobial activity ofcaprylic acid and glyceryl trinitrate (GTN) as a novel non-antibioticantimicrobial combination (Rosenblatt et al., 2013). Caprylic acid (CAP)is a medium chain fatty acid naturally present in human breast milk. CAPhas been used intravenously in some total parenteral nutritionformulations (Wanten and Calder, 2007 and Rayyan et al., 2012). It isalso readily absorbed following oral administration yielding significantblood concentrations (Haidukewych et al., 1982). Protonated CAP has beenreported to have antimicrobial properties (Skrivanova and Marounek, 2007and Yang et al., 2010). The pK of CAP has been reported as approximately4.8 (CRC. Handbook of Chemistry and Physics. 85 ed. New York, N.Y.: CRCPress; 2004-2005).

In some aspects, the compositions described herein comprises one or moremedium chain fatty acid or monoglyceride. In some embodiments, the fattyacid is a saturated fatty acid. A medium chain fatty acid ormonoglyceride is a C₆-C₁₂ alkanoic acid or a glycerol ester of a C₆-C₁₂alkanoic acid. Some non-limiting examples of medium chain fatty acidsinclude caproic acid, caprylic acid, capric acid, or lauric acid. Insome embodiments, the composition comprises caprylic acid. In someembodiments, the medium chain fatty acid (e.g., caprylic acid) ispresent in the antimicrobial composition in its protonated or free acidform

In some aspects, the compositions described herein comprise at least0.1% of the medium chain fatty acid or monoglyceride. The compositionsthat may be used in the present disclosure comprise from about 0.1% toabout 5%, from about 0.1% to about 1%, or from about 0.1% to about 0.5%of the medium chain fatty acid or monoglyceride. In some embodiments,the amount of the medium chain fatty acid or monoglyceride is from about0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, to about 0.5%, or any rangederivable therein. The amount of the medium chain fatty acid ormonoglyceride that may be used is about 0.1% or 0.4%.

In some aspects, the composition comprise both a medium chain fatty acidor monoglyceride and a polygalacturonic acid. In some embodiments, theamounts of each component when formulated together in a composition eachcomprise the amounts described above. In a non-limiting examples, thecompositions may comprise from about from 0.5% to 10%, from 0.5% to 5%,from 0.5% to 3%, from 0.5% to 2%, or about 1% of the polygalacturonicacid and from about 0.1% to about 5%, from about 0.1% to about 1%, orfrom about 0.1% to about 0.5% of the medium chain fatty acid ormonoglyceride.

The pH of the antimicrobial composition may be present at or adjusted toa pH (e.g., a pH of about 4.8 or less) so that the fatty acid (e.g., thecaprylic acid) is protonated or in a free acid state. In someembodiments, the pH of the antimicrobial composition is about 3.5-4.8,more preferably about 3.7-4.8, or 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0 or any range derivable therein.In some preferred embodiments, the

C. Additional Antimicrobial Components

In some aspects, the present composition further comprises anotherantimicrobial component such as a nitric oxide donor, an alcohol, and/ora peroxide. Some non-limiting examples of these antimicrobial componentsinclude hydrogen peroxide, magnesium, calcium, strontium, barium,lithium, potassium, sodium peroxide, glyceryl trinitrate, isosorbidemononitrate, pentaerythrityl tetranitrate, S-nitrosoglutathione,S-nitroso-N-acetylpenicillamine, S-nitroso-captopril, sodiumnitroprusside, S-nitroso-N-valerylpenicillamine, spermine NONOate, anessential oil, or ethanol.

Antimicrobial compositions composition comprise about 0.01%-10%, about0.1%-10%, about 0.1% to about 5%, from about 0.01% to 0.1%, from about0.01% to about 0.05%, from about 0.1% to about 1%, from about 0.1% toabout 0.5%, or about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.2%,0.3%, 0.4%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, or any range derivabletherein of the additional antimicrobial component, such as a peroxideand/or a nitric oxide donor. For example, an antimicrobial compositioncomprising the polygalacturonic acid and the fatty acid may furthercomprise about 0.1-2% (e.g., 0.3%) hydrogen peroxide, glyceryltrinitrate (e.g., at a concentration of about 0.05-1500, 1-1000, or10-500 micrograms/ml), and/or a chelator (e.g., citrate, MeSNA, EDTA,disulfiram; for example, at a concentration of about 0.1-10%, or 1%, 2%,3%, 4%, 5%, 6%, or 7% (v/v) or any range derivable therein).

In some embodiments, a glyceryl nitrate (e.g., glyceryl trinitrate,glyceryl dinitrate, glyceryl mononitrate) may be present in anantimicrobial composition or solution of the present invention in anamount of about 0.05-2000, 0.1-2000, 0.1-1750, 0.1-1500, 0.1-1250,0.1-1000, 1-1000, 10-500, 25-500, 25-250, 50-500, 75-150, or about 10,20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170,180, 190, or 200 micrograms/ml, or any range derivable therein. In someembodiments, intermediate concentrations such as, e.g., 11, 12.5, etc.are contemplated. For example, the concentration of the glyceryl nitratemay be greater than about 10, 11, 12, 13, 14, 15, 20, or 25micrograms/ml. In some embodiments, the glyceryl nitrate may be in aconcentration less than about 2000, 1750, 1500 micrograms/ml. In someembodiments, about 50-125 or about 100 micrograms/ml glyceryl nitratemay be included in a antimicrobial composition (e.g., a catheter lockingsolution, spray, cream, ointment, preparation for topical application tothe skin or a wound, etc.) as these concentrations can be safely usedclinically. In some preferred embodiments, the glyceryl nitrate is GTN.

Glyceryl nitrates include mono-, di-, or trinitrates (e.g., glycerylmononitrate, glyceryl dinitrate, or glyeryl trinitrate). Mixtures ofglyceryl mononitrate, glyceryl dinitrate, and/or glyeryl trinitrate maybe used in various embodiments of the present invention. GTN is alsoreferred to as nitroglycerin, nitroglycerine, trinitroglycerin,trinitroglycerine, 1,2,3-trinitroxypropane, and glyceryl trinitrate.

A variety of chelators may be used with the present invention. Forexample, the chelator may be citrate, a tetra acetic acid, an EDTA, athiosulfate, N-acetyl cysteine, disulfiram, a hydroxy acid, a hydroxamicacid, ethylene diaminedisuccinate (EDDS), Tetrakis hydroxymethylphosphonium sulfate (THPF), or MesNA. The chelator may be citrate. Thechelator may be ethylene diaminedisuccinate (EDDS) or Tetrakishydroxymethyl phosphonium sulfate (THPF). In some embodiments, thechelator is a hydroxy acid, such as an α-hydroxy acid. The hydroxy acidmay be lactic acid, gluconic acid, glycolic acid, galacturonic acid,salicylic acid, or glucaronic acid. In some embodiments, the chelator isa hydroxamic acid. The hydroxamic acid may be hydroxamic acid,benzohydroxamic acid, salicylhydroxamic acid, or suberoylanilidehydroxamic acid (SAHA). The chelator may be, e.g., EDTA free acid, EDTA2Na, EDTA 3Na, EDTA 4Na, EDTA 2K, EDTA 2Li, EDTA 2NH₄, EDTA 3K,Ba(II)-EDTA, Ca(II)-EDTA, Co(II)-EDTACu(II)-EDTA, Dy(III)-EDTA,Eu(III)-EDTA, Fe(III)-EDTA, In(III-EDTA, La(III)-EDTA, CyDTA, DHEG,diethylenetriamine penta acetic acid (DTPA), DTPA-OH, EDDA, EDDP, EDDPO,EDTA-OH, EDTPO, EGTA, HBED, HDTA, HIDA, IDA, Methyl-EDTA, NTA, NTP,NTPO, O-Bistren, TTHA, EGTA, DMSA, deferoxamine, dimercaprol, zinccitrate, a combination of bismuth and citrate, penicillamine, succimeror Etidronate. It is contemplated that a chelator which binds barium,calcium, cerium, cobalt, copper, iron, magnesium, manganese, nickel,strontium, or zinc may be included in various embodiments of the presentinvention.

The antimicrobial composition may comprise an alcohol. For example, theantimicrobial composition may comprise a C₁₋₄ alcohol at a concentrationof about 1-30%, 2.5-25%, 5-25%, 5-15%, 10-15%, 5-10%, 10-30%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45% or any range derivable therein (e.g., in acatheter flush or lock solution, an ointment, cream, spray, solution,etc.). The C₁₋₄ alcohol may be ethanol, isopropanol, methanol, orbutanol. In some preferred embodiments, the C₁₋₄ alcohol is ethanol orisopropanol. In some embodiments, the alcohol may be cyclohexanol,benzyl alcohol, chlorobutanol, 2-bromo-2-nitropropan-1,3-diol, orphenylethyl alcohol. In some embodiments, higher concentrations of analcohol (e.g., greater than 50%) may be used in various embodiments,e.g., on the surface of a device or prosthetic or where the alcohol maybe reasonably tolerated by a subject (e.g., when used for application tothe skin. Nonetheless, in some embodiments, lower concentrations of analcohol may be preferable since little or no irritation may result fromlower concentrations of alcohol (e.g., when used as a catheter lock orflush solution).

In some embodiments, an antimicrobial composition of the presentinvention does not include an antibiotic; for example, antibioticresistance has emerged as a problem in clinical settings, and in someembodiments it may be beneficial to exclude an antibiotic from anantimicrobial composition of the present invention. Nonetheless, in someembodiments, it may be desirable to include one or more antibiotics inan antimicrobial composition of the present invention. A variety ofantibiotics may be used with the present invention. In some embodiments,the antibiotic is trimethoprim and/or minocycline. For example, one ormore antibiotic agent(s) may be included in an antimicrobial compositionof the present invention, such as, e g, aminoglycosides, beta lactams,quinolones or fluoroquinolones, macrolides, sulfonamides,sulfamethaxozoles, tetracyclines, streptogramins, oxazolidinones (suchas linezolid), clindamycins, lincomycins, rifamycins, glycopeptides,polymxins, lipo-peptide antibiotics, as well as pharmacologicallyacceptable sodium salts, pharmacologically acceptable calcium salts,pharmacologically acceptable potassium salts, lipid formulations,derivatives and/or analogs of the above. The antibiotic may be a memberof the penicillin group of antibiotics such as, e.g., amoxicillin,ampicillin, benzathine penicillin G, carbenicillin, cloxacillin,dicloxacillin, piperacillin, or ticarcillin, etc. Examples ofcephalosporins include ceftiofur, ceftiofur sodium, cefazolin, cefaclor,ceftibuten, ceftizoxime, cefoperazone, cefuroxime, cefprozil,ceftazidime, cefotaxime, cefadroxil, cephalexin, cefamandole, cefepime,cefdinir, cefriaxone, cefixime, cefpodoximeproxetil, cephapirin,cefoxitin, cefotetan etc. Examples of beta lactamase inhibitors includeclavulanate, sulbactam, or tazobactam. The antibiotic may be a macrolidesuch as, e.g., erythromycin, azithromycin, or clarithromycin. Examplesof quinolones and fluoroquinolones that may be used include nalidixicacid, cinoxacin, trovafloxacin, ofloxacin, levofloxacin, grepafloxacin,trovafloxacin, sparfloxacin, norfloxacin, ciprofloxacin, moxifloxacinand gatifloxacin. Examples of sulphonamides that may be used includemafenide, sulfisoxazole, sulfamethoxazole, and sulfadiazine. Thestreptogramin class of antibacterial agents is exemplified byquinupristin, dalfopristin or the combination of two streptogramins.Drugs of the rifamycin class typically inhibit DNA-dependent RNApolymerase, leading to suppression of RNA synthesis and have a verybroad spectrum of activity against most gram-positive and gram-negativebacteria including Pseudomonas aeruginosa and Mycobacterium species. Anexemplary rifamycin is rifampicin. Other antibacterial drugs areglycopeptides such as vancomycin, teicoplanin and derivatives thereof.Yet other antibacterial drugs are the polymyxins which are exemplifiedby colistin. In addition to these several other antibacterial agentssuch as prestinomycin, chloramphenicol, trimethoprim, fusidic acid,metronidazole, bacitracin, spectinomycin, nitrofurantion, daptomycin orother leptopeptides, oritavancin, dalbavancin, ramoplamin, ketolide etc.may be used in preparing the compositions described herein.

It is also contemplated that any additional pharmacologically activeingredients or sterilization agents may be included in an antimicrobialcomposition of the present invention or may be used in combination withan antimicrobial composition of the present invention to further reduceor eliminate pathogenic microbes and viruses. Typical pharmacologicallyactive ingredients include antifibrin agents, anti-thrombotic agents,and anti-inflammatory agents. Anti-inflammatory agents include steroids,and nonsteroidal anti-inflammatory agents, and salicylates.Anti-thrombotic drugs include acetylsalicylic acid, dipyridamole,heparin, ibuprofen, indomethacin, prostaglandins, sulfinpyrazone,warfarin, thrombolytic enzymes such as streptokinase, urokinase, orplasminogen activator. Complexing agents such as ammonium-1-pyrrolidinedithiocarbanate may also be used. However, the above examples are notmeant to be limiting. In some embodiments, an antimicrobial compositionas described herein may comprise one or more additional anticoagulantand/or an anti-inflammatory agent.

An antimicrobial compositions of the present invention (e.g., anantimicrobial solution, ointment, cream, spray, solution, catheter lockor flush solution) as described herein, may contain an additional agentdissolved or dispersed in a pharmaceutically acceptable carrier. Thephrases “pharmaceutical or pharmacologically acceptable” refers tomolecular entities and compositions that do not produce an adverse,allergic or other untoward reaction when administered to an animal, suchas, for example, a human, as appropriate. An antimicrobial compositionas described herein may contain an additional active ingredient, e.g.,as exemplified by Remington: The Science and Practice of Pharmacy,21^(st) Ed., Lippincott Williams and Wilkins, 2005, incorporated hereinby reference. Moreover, for animal (e.g., human) administration, it willbe understood that preparations should typically meet sterility,pyrogenicity, general safety and purity standards as required by FDAOffice of Biological Standards.

III. CLEANING OR DISINFECTING MEDICAL DEVICES

In addition to use with catheters (e.g., as a catheter lock solution ora catheter flush solution), an antimicrobial composition or solution ofthe present invention may be applied to or used with a medical device.In some embodiments, the antimicrobial composition is used as a catheterlock solution, e.g., with a Foley catheter, a Lerman Foley catheter, ora double balloon catheter.

The medical device may be, e.g., an endotracheal tube, a nephrostomytube, a feeding tube, a gastric tube, a nasal tube, a biliary stent, anorthopedic device, a valve, a prosthetic valve, a drainage tube, adrain, a shunt, a staple, a clip, a mesh, a film, a blood exchangingdevice, a port, a cardiovascular device, a defibrillator, a pacemakerlead, a wire coating, an ocular implant, an auditory implant, a cochlearimplant, a dental implant, a stimulator, a drug delivery depot, afilter, a membrane, a vascular access port, a stent, an envelope, a bag,a sleeve, intravenous or other tubing, a bag, a dressing, a patch, afiber, a pin, a vascular graft, a suture, a cardiovascular suture, or animplantable prosthesis. In some embodiments, the medical device is acatheter such as, e.g., a vascular catheter, a urinary catheter, anintracranial catheter, an intraspinal catheter, a peritoneal catheter, acentral nervous system catheter, a cardiovascular catheter, a drainagecatheter, a soaker catheter, an aspirating catheter, an intrathecalcatheter, a neural catheter, a vaginal catheter or tube, a uterinecatheter or tube, a stimulating catheter, or an epidural catheter. Thecatheter may be a vascular catheter such as, e.g., a central venouscatheter, an arterial line, an pulmonary artery catheter, a peripheralvenous catheter, an intravenous catheter, or an intraarterial catheter.

Medical devices that are amenable to treatment according to a method ofthe present invention generally include non-metallic materials, such asrubber, plastic, polyethylene, polypropylene, polyurethane, silicone,polytetrafluoroethylene (PTFE), polyethylene terephthalate (PET), latex,nitrile, and other polymeric and elastomeric materials (e.g., collagens,gelatins, crosslinked collagens, crosslinked gelatins, hyaluronates,chitosams, alginates, allografts, xenografts, autografts), as well asmetals, such as titanium, and metal alloys, such as stainless steel andnitinol. Those skilled in the art will appreciate that the listing ofnon-metals, metals, and metal alloys as described herein is exemplaryonly, and is not intended to be exclusive. Other materials that areamenable to treatment as described herein are also within the scope ofthe present invention.

In some embodiments, an antimicrobial composition is used to clean orrinse a medical device. Nonetheless, in some embodiments, the medicaldevice may be washed following contact with the antimicrobialcomposition.

Additional details regarding contacting an antimicrobial with a medicaldevice not specifically recited herein can be found, e.g., in U.S. Pat.Nos. 5,217,493, 5,624,704, 5,902,283, and 7,651,661, as well as in U.S.Patent App. Pub. Nos. 2005/0197634, 2003/0078242, 2007/0154621,2008/0183152, 2010/0055086, 2011/0201692, and 2012/0064372 allincorporated by reference.

Referring now to FIG. 5, an exemplary embodiment is shown of a drainagedevice that can be used in conjunction with the antimicrobialcompositions disclosed herein. In this embodiment, the drainage deviceis configured as a catheter 100. In particular embodiments, catheter 100may be configured as a urinary catheter comprising a first end 101 (e.g.a proximal end close to a urine collection container) and a second end102 (e.g. a distal end extending into the bladder). Catheter 100comprises a central lumen 105 that extends between proximal end 101 anddistal end 102 and allows for fluid to be drained from the bladder (orother location within the body) to the collection container.

In the embodiment shown, catheter 100 also comprises a proximalreservoir 110 and a distal reservoir 120. In certain embodiments,proximal reservoir 110 may be an irrigation cuff and distal reservoir120 may be a retention cuff. A first conduit 111 and inlet port 112 arein fluid communication with proximal reservoir 110, while a secondconduit 121 and inlet port 122 are in fluid communication with distalreservoir 120. In this embodiment, inlet ports 112 and 122 are locatedproximal to first end 101 to allow a user to direct fluids (includingliquids or gas, such as air) through first and second conduits 111 and121. In certain embodiments, inlet ports 112 and 122 may each comprise avalve that can be opened or closed to control flow.

For example, a user can couple an irrigation fluid container 113 (e.g.,a syringe) to inlet port 112 and open inlet port 112 during or after theinsertion of catheter 100. The irrigation fluid can be directed throughconduit 111 toward second end 102 and into proximal reservoir 110 ofcatheter 100. Proximal reservoir 110 comprises outlet ports 115 (e.g.openings in the reservoir such as holes or slits) configured to dispenseirrigation fluid from proximal reservoir 110.

When catheter 100 inserted to the desired depth, a user can couple apressure source 123 (e.g., a syringe or other suitable device) to inletport 122, which can then be opened to inflate distal reservoir 120 viaconduit 121. In certain embodiments, inlet port 122 may comprise a valvethat can be opened or closed to control the inflation of distalreservoir 120. When inflated, distal reservoir 120 can retain second end102 of catheter 100 in the bladder.

In exemplary embodiments, the irrigation fluid directed through conduit121 may comprise an antimicrobial composition as disclosed herein. Inspecific embodiments, the irrigation fluid may comprise synergisticantimicrobial compositions with low toxicities comprising partiallyesterified polygalacturonic acid and fatty acids that could be appliedto disinfect tissues or surfaces of catheter 100. In particularembodiments, the irrigation fluid could be intermittently applied insitu to irrigate the external surface of catheter 100 in contact withthe urethra 147.

In other embodiments, different types of devices may be used inconjunction with the irrigation fluid, including for example, drainagedevices comprising surgical drains, drainage catheters such asnephrostomy tubes, shunts and catheters such as urinary catheters.Exemplary drainage devices comprise at least one lumen that can conductfluid from a cavity, organ or tissue inside of the body to a collectioncontainer outside of the body. The collection container can be a bag orvessel, an absorbent medium or could be returned to another part of thebody.

In general, drainage through central lumen 105 occurs passively (withoutapplied pressure or suction), but active drainage can occur throughapplication of pressure, squeezing or other forces or by suction.Catheter 100, in addition to having one or more lumens, also has atleast one wall 145 (disposed around central lumen 105) with an outersurface 140. Outer surface 140 may not directly contact the drainingfluid through central lumen 105.

Outer surface 140, however, is in contact with tissues or conduits untilit traverses the skin to outside of the body where it typically connectsto a bag, reservoir or absorbent medium. Outer surface 140 can causeirritation if it rubs against tissues it passes through. Outer surface140 can also become colonized by pathogenic microbes and can thereforebe a source of infection. The ability to irrigate outer surface 140 withmedicated, lubricious or adhesive fluids via outlet ports 115 cantherefore be beneficial. In some cases the medicated fluid can bedisinfecting and additionally can contain other medications such as painrelievers, antifibrotic or mucolytic medications, or collagenolyticagents (to treat strictures for example), and in some embodiments themedicated fluid may optionally include one or more fragrances to maskodors. Of particular interest are the antimicrobial compositions asdisclosed herein.

For the case where catheter 100 is a urinary catheter, outer surface 140would contact the surface tissues of urethra 147. The irrigating fluidwould then reside between outer surface 140 and urethra 147. Alubricious fluid could help reduce urethral mechanical trauma and anantimicrobial fluid could prevent microbes from colonizing the externalsurface of the urinary catheter into the bladder and beyond.

The urethra is distensible when pressure is applied but typically is ina collapsed resting state. When a urinary drainage catheter is inserted,the urethra will normally collapse around the external surfaces of thecatheter. In order to irrigate the urethra, a pressure gradient directedfrom urethral-bladder 149 junction towards meatus 148 is preferred.Irrigation fluid can then flow down the pressure gradient betweenurethra 147 and external surface 140 of catheter 105 until it exits atmeatus 148. Meanwhile, the urinary drainage function is performed bycentral lumen 105, which provides a conduit from the bladder to outsideof the body.

In the embodiment shown in FIG. 5, distal reservoir 120 can beconfigured as a retention cuff or balloon to secure catheter 100 nearthe drainage entry point following insertion. Other securement meansinside the body near the drainage entry point are also possibleincluding, clips, springs, string, bands, prongs, staples, glues,adhesives etc. Drainage catheters can also be secured the exit site,although if not also secured at the drainage entry point, a risk ofmigration of the tip of the drainage catheter exists. The externalsurface irrigation devices described herein can work with any suitablesecurement means.

In certain embodiments, catheter 105 may configured similar to a Foleycatheter where distal reservoir 120 is configured as a securementballoon. With this configuration, the securement balloon is below thetip and can be inflated such that central lumen 105 is unaffected. Theinflated balloon surface can extend outward from outer surface 140. Incertain embodiments, lumen 121 can be embedded in wall 145 of catheter105. Catheter 105 can be inserted in a deflated state and is inflatedonly when the distal end 102 has been inserted into the bladder. Thediameter of the distal reservoir 120 is larger than the diameter of theurethral bladder junction so that distal end 102 is maintained in thebladder by the physical entrapment of the inflated distal reservoir 120(e.g. cuff) at urethral bladder junction 149. In certain embodiments,catheter 100 may have an additional balloon or cuff at the tip in thebladder to reduce trauma from the tip to the bladder wall.

In certain embodiments of catheter 105, proximal reservoir 110 isconfigured as balloon just below urethral bladder junction 149. In oneembodiment, the balloon is comprised of an elastomeric material.Silicone, latex, nitrile, urethane or fluoroelastomers are examples ofmaterials from which proximal reservoir 110 can be made. In certainembodiments outlet ports 115 (e.g. holes or slits) at its proximal basedirected down the shaft towards the meatus.

Outlet ports 115 can be arranged circumferentially at the base of theproximal reservoir 110 so as to distribute irrigating fluid uniformlyaround outer surface 140 of catheter 105. As previously described,irrigation fluid can injected into proximal reservoir 110 through inletport 112 using irrigation fluid container 113 (e.g. a syringe) that canpump fluid under positive pressure. Inflating proximal reservoir 110with pressurized fluid causes it to temporarily expand. In certainembodiments, there is a one-way valve between the inlet port 112 andirrigation fluid container 113 preventing backflow. The expandedproximal reservoir (e.g. irrigation cuff) pushes on the fluid forcing itthrough outlet ports 115 at the base of the cuff. Over time, thepressure is relieved as the irrigating fluid is pumped down urethra 147towards meatus 148.

In exemplary embodiments, first reservoir 110 (e.g. the irrigation cuff)can be molded and bonded to the shaft of catheter 100 above and belowwhere outlet ports 115 exit the catheter wall 145 to outer surface 140.In certain embodiments, the holes or slits can be pre-formed prior toadhering to the shaft or can be formed by inflating the cuff with afluid, changing the temperature to freeze or gel the fluid to a solid,poking the holes with the solidified inflation fluid and then warming upto where the inflating fluid liquefies and exits the system. An exampleof such an inflation fluid is a gelatin solution, where the fluid isinstilled at a temperature above 40 degrees Celsius to inflate theirrigation cuff, taken to refrigeration at 4 degrees Celsius where thefluid solidified, holes are poked at the base of the irrigation cuff inthe solidified state and the assembly is reheated to near 40 degreesCelsius and the gelatin solution is evacuated and flushed out.

The irrigation cuff and/or outlet ports can be fitted with nozzles ordirectional elements that facilitate spraying or directional dischargeof the irrigating solution under pressure. The irrigation cuff can alsobe fitted with miniature valves that can be actuated remotely fordelayed or pulsatile discharge of the irrigating fluid into the spacebetween the urethra and outer wall of the drainage catheter. A pump canbe connected to the inflation valve of the irrigation in order toprovide programmed intermittent or continuous urethral irrigation.

A disposable absorbent element can be secured at meatus 148 to collectirrigating fluid discharged at the meatus along outer surface 140 ofcatheter 100. Examples of absorbent elements are sponges, superabsorbenthydrophilic polymers, fleeces, fabrics, or gauzes. A ribbon of gauze canbe tied around the external catheter surface proximal to meatus 148 andslid up to contact meatus 148. A gauze can also have an adhesive backingor adhesive tabs that can be used to secure it around the externalsurface of the catheter at the meatus. The adhesive backing or tabs canhave pre-cut perforations that make it easy to tear for removal.Similarly, an absorbent sponge (such as a natural, urethane orpolyvinylalcohol based sponge) can be secured around outer surface 140either with adhesive tabs or backing or by preforming to an annularshape with that can form a compression fit around outer surface 140 ofcatheter 100. The absorbent element can also be a strip or film madefrom superabsorbent polymers or can be in granule form. Single pieceannular absorbent elements can contain slits that allow them to be slidover external surfaces of catheters.

In certain embodiments, either a fabric, a film or a sponge can also besecured using magnets that can hold it together as well as to catheter100. The catheter, for example could have a magnetic band at meatus 148which can help secure and adhere the absorbent element or two,half-donut shaped elements can be magnetically secured around thecatheter shaft. Velcro or clips can also be used to secure the absorbentelement. Velcro tabs or clips can be built in to the absorbent elementor can be wrapped around it and then compressed to secure it. Securementcan also be accomplished by the unidirectional ratcheting action of“cable tie” type connectors, harpoon/receiver and similar clamps, prongswith latches and receivers, hooks cords, lanyards, fasteners, twistlocks, ties and tie-downs. The securement clips or ties can bepre-scored to be readily broken apart when desired for removal.

In some embodiments, an elastomeric, or firm, cup-shaped concavecollector can also be secured around outer surface 140 of catheter 100with absorbent material contained within the cup collection space. Theabsorbent element can also have outward-facing convex protrusions whichmight be useful for certain anatomies. Disposable absorbent elements canbe packaged and sold together with irrigation containers such as syringein single-use, disposable, catheter external surface care andmaintenance kits. The irrigation can be performed daily, or multipletimes daily with frequency varied as needed.

One type of irrigation fluid contains the antimicrobial compoundscaprylic acid and polygalacturonic acid described herein. It may alsocontain enhancers such as hydrogen peroxide or nitric oxide donors (likenitroprussides or nitroglycerin). The irrigation fluid may also containviscosity modifying compounds such as thickening agents. The irrigationfluid can contain components that protect urethral tissues. Onecombination is Carboxymethylcellulose and propylene glycol. Theirrigation fluid can be either aqueous-based, lipid-based,polymer-based, or inorganic. The irrigation fluid can also deliverMeSNA, N-acetylcystein, or collagenolytic agents to alleviate stricturesthat might form over extended catheterizations. Similarly, clottingagents for torn urethras and pain-reliving agents such as aspirin orlidocaine can be included in the irrigation fluid.

IV. ANTIMICROBIAL AGENTS AND MICROBES

Antimicrobial compositions of the present invention may be used to kill,destroy, or reduce the proliferation of a variety of microbes. Somenon-limiting exemplary bacterial and fungal microbes that can be reducedor eradicated by the compositions and methods of the invention includeStaphyloccous species (such as Staphylococcus epidermidis),Staphylococcus aureus; Asperigllus species (such as Aspergillus flavus,Aspergillus terreus), Enterrococcus faecalis, Pseudomonas aeruginosa,Escherichia coli, Fusarium oxysporum, and Candida species (such asCandida krusei, Candida parapsilosis, Candida tropicalis, Candidaalbicans and Candida glabrata).

IV. EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Example 1 Synergistic Caprylic and Polygalacturonic Acid Combinationsfor Eradication of Biofilm

There is a need in contaminated dermal and epithelial environments forbroad-spectrum eradication of pathogenic biofilms with biocompatible,non-antibiotic, antimicrobial compositions. In this Example, theinventors observed a rapid and complete biofilm eradication in an invitro model with synergistic combinations of caprylic andpolygalacturonic acids against resistant gram-positive, gram-negative,and fungal biofilms.

In this example, the inventors studied biofilm eradication by the use ofmedical polygalacturonic acid and caprylic acid (PG+CAP) for potentialuse in medical applications. In vitro antimicrobial efficacy of PG+CAPwas assessed in a well-established biofilm colonization model testingeradication of biofilm following different durations of antimicrobialagent exposure. Biofilm eradication was assessed for clinical isolatesof methicillin-resistant Staphylococcus aureus (MRSA),multidrug-resistant Pseudomonas aeruginosa (PS), and Candida albicans(CA) as representative key gram positive, gram negative and fungalinfectious pathogens. Briefly, 1 cm silicone discs were placed in 1 mLof human plasma and incubated overnight at 37° C. The plasma wasreplaced with 1 mL of 5.5×10⁵ CFU/mL inoculum of challenge organism, andincubated for 24 hrs at 37° C. Inoculum was then removed and discs werewashed to remove any planktonic organisms by shaking for 30 minutes in0.9% sterile saline. After washing, discs were exposed to 1 mL of testsolution at 37° C. for 15, 30, 60 or 120 minutes. The discs were thenremoved, placed in 5 mL of 0.9% sterile saline, and sonicated for 15minutes to disrupt any remaining biofilm. The resulting solution wasthen cultured and plated on Trypticase Soy Agar+5% sheep blood(bacteria) or Sabouraud Dextrose Agar (yeast). The upper limit ofquantitation for this assay was 100 colonies, any plate with >100colonies was considered to be “>100,” which, incorporating the dilutionfactor, is represented as 5000 in the final colony counts.

Antimicrobial solutions were prepared containing 1% PG (Sigma-Aldrich StLouis, Mo.<15% esterified)+0.1% or 0.4% CAP (Sigma-Aldrich, St Louis,Mo.). The pH was adjusted to 4.0-4.5. Muller Hinton Broth, 1% PG, 0.1%CAP and 0.4% CAP were included as control solutions. The pH of allsolutions was adjusted to 4.0-4.5 (except the Muller Hinton Brothcontrol). Complete eradication of the biofilm requires a recovery of noviable colonies following treatment. Recovery of fewer viable organismsthan from the control indicates partial eradication of the biofilm. Eachtime point for each organism for each disinfecting solution was testedin triplicate. Results are presented in FIGS. 1A-C. Complete biofilmeradication required that no viable colonies were recovered followingexposure to the test solutions for the specified durations.

As seen in FIGS. 1A-C, protonated CAP has reported weak antimicrobialactivity (Skrivanova and Marounek, 2007 and Yang et al., 2010) and PGalso has reported weak antimicrobial activity (Thakur et al., 1997). Inthis study, a synergistic reduction in the time to biofilm eradicationis seen with the 1% PG+0.1% CAP solution against CA and PS, and for the1% PG+0.4% CAP solution against MRSA, PS and CA. One hypothesis for thesynergy with the 0.1% CAP combination is that the PG binds importantmetal ions and cationic molecules such as peptides while the CAPdisrupts cell membranes. This concentration of CAP (0.1%) is close tothe reported aqueous solubility limit. Without wishing to be bound byany theory, it is envisioned that the enhanced synergy seen with 0.4%CAP might in part be due to apparent solubility enhancement of CAP inthe PG+CAP combination. At 0.4% concentration, CAP alone (without PG)showed visible signs of phase separation or immiscibility. Withoutwishing to be bound by any theory, the inventors anticipate that thepartial esterification of the polygalacturonic acid might be importantor necessary for balancing the two effects of enhancing the apparentsolubility of the CAP while simultaneously binding critical cations.

Efficacy of 1% PG+0.1% CAP in eradicating biofilm was statisticallysignificant relative to both 1% PG alone (p=0.0034) and 0.1% CAP alone(p=0.0034) for MRSA within 1 hour of exposure. Efficacy of 1% PG+0.4%CAP in eradicating biofilm was statistically significant for MRSA (1hour), PS (30 min), and CA (1 hour) relative to 1% PG along (p=0.0021,p=0.0078, and p<0.001, respectively) and 0.4% CAP alone (p=0.0462,p=0.0109, and p=0.0297, respectively).

CAP is a naturally occurring fatty acid; in the deprotonated state(neutral pH), caprylate ion has a well-established metabolic profile asa nutrient in mammals (Hirabara et al., 2006). Deprotonating CAP can beaccomplished by raising the pH above 4.8 (CRC. Handbook of Chemistry andPhysics. 85 ed. New York, N.Y.: CRC Press; 2004-2005), hence in mostphysiological environments CAP will rapidly become deprotonated to abenign nutrient once the local pH increases. In a pharmaceuticalformulation the antimicrobial protonated CAP state can be maintainedwith pH below 4.8. This pH falls within range for natural skin pH seenin humans (Lambers et al., 2006). Additional epithelial environmentssuch as the vaginal canal (Lang 1955) and digestive tract (Evans et al.,1988) maintain an acidic pH. Caprylic acid has been reported to aid inwound healing (Srivastava and Durgaprasad, 2008 and Pieper and Caliri,2003). PG has been widely used in hydrocolloid wound dressings withreported benefits of maintaining a moist, acidic environment andproviding a bacterial barrier and is in several commercial wound healingsheet and paste products (Munarin et al., 2012).

Next, PG+CAP combinations were tested using a quantitative assessment ofbiofilm eradication for PG, CAP and PG+CAP solutions. To assess anypotential antimicrobial activity of PG, minimum inhibitory concentration(MIC) assays were conducted. MICs were determined by microbrothdilutions in accordance with CSLI M07 guidelines ((CLSI) CaLSI.M07-A10-Methods for Dilution Antimicrobial Suseptibilty Tested forBacteria that Grow Aerobically; Approved Standard-Tenth Edition. Volume35. Wayne, Pa.2015). MRSA, Pseudomonas aeruginosa and Candida albicanswere exposed to a range of dilutions of PG (0%, 0.25%, 0.5%, 0.75% and1%). MIC was determined by visual scoring for growth. The well with thelowest concentration of drug in which no turbidity was observedcorresponded with the MIC for the organism tested.

For MRSA inhibition occurred at PG concentrations above 0.5%. ForPseudomonas aeruginosa inhibition occurred at PG concentrations above0.75% and for Candida albicans growth was not inhibited at PGconcentrations of 1% or less.

In vitro antimicrobial assessments of PG, CAP, and PG+CAP solutions wereconducted using an established time-to-kill biofilm eradication model,the modified Kuhn's model (Kuhn et al., 2002). Briefly, 1 cm diametersilicone discs, were placed into a 24-well tissue culture plate andincubated with donor human plasma at 37° C. for 24 hours. The plasma wasthen removed, replaced with 1 mL of 5.5×10⁵ CFU of bacterial (MRSA,Pseudomonas aeruginosa) or yeast (Candida albicans) inocula andincubated at 37 C for an additional 24 hrs. Inoculum was removed and thediscs were washed shaking at 100 rpm for 30 minutes in 0.9% sterilesaline in order to remove any planktonic organisms. After washing, discswere exposed to 1 mL various disinfectant solutions and incubated at 37°C. for 30 min or 60 min. Saline flush solution was used a negativecontrol. Subsequently, discs were removed and placed in 5 mL of 0.9%sterile saline and sonicated (60 Hz and 150 W) for 15 minutes to disruptany remaining biofilm. Resulting solutions were quantitatively culturedby plating 100 μL onto Muller-Hinton (for bacteria) or Sabourauddextrose (for yeast) agar. Antimicrobial solutions were preparedcontaining 1% PG (Sigma-Aldrich St Louis, Mo.<15% esterified)+ either0.1% or 0.4% CAP (Sigma-Aldrich, St Louis, Mo.). The pH was adjusted to4.0-4.5. Muller Hinton Broth, 1% PG, 0.1% CAP and 0.4% CAP were includedas control solutions. The pH of all solutions was adjusted to 4.0-4.5(except the Muller Hinton Broth control). Complete eradication of thebiofilm requires a recovery of no viable colonies following treatment.Recovery of fewer viable organisms than from the control indicatespartial eradication of the biofilm. All biofilm eradication experimentswere performed with 6 replicates, and results are shown in FIGS. 2A-C.

As shown in FIGS. 2A-C, 1% PG+0.4% CAP was able to fully eradicate MRSAbiofilms at 60 minutes, Pseudomonas aeruginosa biofilm at 30 minutes andCandida albicans biofilm at 60 minutes. None of the other solutions wereable to fully eradicate biofilms in these time frames.

Statistical analyses: The Kruskal-Wallis test was used to determinewhether there was a significant difference in the medians in any of thelock solutions tested. Pairwise comparisons were assessed using theMann-Whitney U test to cm performance of PG+CAP and CAP lock solutionsat specified time points. All tests were 2-sided with an alpha level of0.5. A P-value less than 0.05 (p<0.05) was utilized to determinestatistical significance.

TABLE 1 Statistical Results MRSA - 60 min Mann-Whitney - pairwisecomparisons - 2-tailed 1% PG + 0.4% CAP vs Control p = 0.002 1% PG +0.4% CAP vs 1% PG p = 0.002 1% PG + 0.4% CAP vs 0.4% CAP p = 0.180Pseudomonas aeruginosa - 30 min Mann-Whitney - pairwise comparisons -2-tailed 1% PG + 0.4% CAP vs Control p = 0.002 1% PG + 0.4% CAP vs 1% PGp = 0.015 1% PG + 0.4% CAP vs 0.4% CAP p = 0.041 Candida albicans - 60min Mann-Whitney - pairwise comparisons - 2-tailed 1% PG + 0.4% CAP vsControl p = 0.002 1% PG + 0.4% CAP vs 1% PG p = 0.002 1% PG + 0.4% CAPvs 0.4% CAP p = 0.015

At 60 minutes for MRSA, the reductions in viable cells for the 1%PG+0.4% CAP treated samples were significant compared to control and 1%PG. 0.4% CAP was able to reduce, but not completely eradicate viableMRSA organisms in the biofilm with this exposure. At 30 minutes forPseudomonas aeruginosa the reductions in viable cells for the 1% PG+0.4%CAP treated samples were significant compared to control, 1% PG, and0.4% CAP demonstrating synergy in eradicating Pseudomonas aeruginosabiofilm. At 60 minutes for Candida albicans, the reductions in viablecells for the 1% PG+0.4% CAP treated samples were significant comparedto control, 1% PG, and 0.4% CAP, demonstrating synergy in eradicatingCandida albicans biofilm.

In conclusion, the inventors observed that PG-CAP combinations arecapable of rapidly eradicating gram positive, gram negative and fungalbiofilms within 1 hour. This synergistic, non-antibiotic, antimicrobialcombination may be used for treating and/or eradicating pathogenicbiofilms in medical applications, such as contaminated wounds.

Example 2 Non-Antibiotic Wound Ointment for Chronic Wound Therapy

An ointment consisting of a combination of agents includingnitroglycerin, caprylic acid, and pectinic acid may be applied topicallyon the skin of a human patient, and details regarding clinical trialsare presented below. Based on the known properties of the individualcomponents, it is anticipated that the use of the combination ofnitroglycerin, caprylic acid and pectinic acid will be safe when used inclinically for topical application to the skin. Furthermore, as shown inthe above Example, in vitro testing has shown that this mixture aresynergistic and highly effective in rapidly eradicating resistant grampositive, gram negative and fungal pathogens embedded in biofilms.

A wound ointment containing nitroglycerin, caprylic acid, and pectinicacid may be used for the topical treatment of chronic wounds thatincludes venous, arterial, diabetic, and pressure ulcers. Thisantimicrobial wound ointment with its effect on bacterial killing andincreasing blood flow of chronic wounds, targets the important elementsand may achieve effective and long-lasting results in the management ofpatients with chronic wounds. An open-label randomized trial will beperformed. Patients presenting with chronic wound including any of thefollowing venous, arterial, diabetic, and pressure ulcers will berandomized to two equal groups: Group 1 will receive the antimicrobialwound ointment, Group 2 will receive the commercially availableMEDIHONEY™ ointment as the comparator. The groups will be comparedduring 12 weeks of treatment for extent of wound-closure, microbialburden, pain and treated-related adverse events. This clinical studywill generate preliminary robust data to that may be used to supportsubsequent future large multicenter clinical trial for the management ofchronic wound in cancer patients.

To further assess its clinical utility in healing microbiallycontaminated wounds, we propose to accomplish the following specificaims in a pilot clinical trial:

(1) To clinically demonstrate reduced microbial burden in wound beds,decrease pain and improved wound closure (such as >50% reduction inwound area) at 6 and 12 weeks with the use of the novel antimicrobialwound ointment versus standard of care wound treatment that includehoney.

(2) To clinically demonstrate that the novel antimicrobial woundointment is well tolerated and safe on wounds as compared to thestandard of care ointment.

Microbial contamination of wounds acquired as a result of injury ordisease delays healing (Siddiqui and Bernstein, 2010 and Robson 1997).Additional factors complicating healing of infected wounds includevascular disruption which limits delivery of systemically-administeredagents to the site of infection, and development of bacterial biofilmsin chronically-infected wounds. Biofilms are an essential defensemechanism for microbes, consisting of a 3-dimensional architecture andexopolysaccharide matrix which protects the microbes within from hostimmune cells, antibodies and antibiotics, and also promotes resistanceto antimicrobial therapies. To eliminate biofilm-related infections, itis necessary to penetrate the protective architecture of the biofilmwith antimicrobial agents capable of eradicating culprit organisms.

Honey has been used for millennia to aid in healing chronic wounds.Honey exerts several beneficial effects in wounds (6,7) includingmaintaining an acidic pH (of about 4) through the presence of organicacids, maintaining surface hydration and osmotically debriding woundsthrough its high sugar content, and inhibiting microbes through releaseof hydrogen peroxide and presence of other antimicrobial agents (such asmethyglyoxal in Manuka honey). Twenty six human clinical trials ofhoney-based wound treatment have been recently reviewed (8) and showeduneven outcomes. Honey effectively accelerated healing in partialthickness burn wounds and in infected surgical wounds but gave limitedevidence of benefit in healing of chronic wounds, pressure and venousulcers as well as diabetic foot ulcers. MEDIHONEY™ (DermaSciences Inc.,Princeton, N.J.) is an FDA approved wound ointment that has beensubjected to clinical testing relative to standard wound dressingtreatments (9,10). MEDIHONEY™ has been reported to reduce pain andnecrosis; however, it showed a non-significant trend towardsaccelerating healing of mixed chronic wounds. Despite some promisingstudies with honey as an improvement over treatment with standarddressings, there remains a need for an improved antimicrobial woundointment that can significantly improve outcomes with microbiallycontaminated chronic wounds.

Data on Antimicrobial Synergy of GTN

Biofilm eradication experiments on caprylic acid-pectinic acidcombinations were conducted using the Modified Kuhns Biofilm EradicationModel (Rosenblatt et al., 2015). Methicillin resistant Staphylococcusaureus (MRSA), Pseudomonas aeruginosa (PS), Candida albicans (CA) andCandida glabarata (CG) were selected as representative virulent grampositive, gram negative and fungal pathogens causing wound infectionsfor testing. Disinfecting solutions tested in this experiment were 1%pectinic acid, 0.4% Caprylic acid, 0.03% GTN. pH of all disinfectingsolutions was adjusted to 4.0-4.5 (same pH range as honey). Reportedresults are the times (in minutes) to complete biofilm eradication usingthe biofilm eradication procedure described above. For biofilms thatwere not completely eradicated within 120 minutes exposure to adisinfecting solution the result is reported as greater than (>) 120minutes:

TABLE 2 Disinfecting Solution MRSA PS CA CG 1% Pectinic Acid (PG) >12060 >120 >120 0.4% Caprylic Acid (CAP) 120 60 120 60 1% PG + 0.4% CAP 6015 30 60 0.03% nitroglycerin (GTN) >120 >120 >120 >120 1% PG + 0.4%CAP + 0.03% GTN 60 15 30 15

Data on Catheter Disinfecting Solution Containing CAP/PG and HydrogenPeroxide

Disinfecting solutions consisting of 0.3% hydrogen peroxide (H2O2), 1%PG+0.4% CAP+0.3% H2O2 in 1.5% CMC vehicle were applied around the topexternal surface and allowed to flow down the external shafts of urinarycatheters for a transient contact exposure of a few minutes. Theexternal surfaces had been exposed during the previous 24 hours toeither methicillin resistant Staphylococcus aureus (MRSA), Escherichiacoli (E. coli), vancomycin resistant Enterococcus (VRE) or Candidaalbicans (C. albicans) as colonizing organisms. 1.5% carboxymethylcellulose (CMC solution) was used as a control. Median recoveries (inCFU/cm of catheter) from three 1 cm catheter segments are tabulatedbelow:

TABLE 3 Disinfecting Solution E. C. (in 1.5% CMC solution) MRSA coli VREalbicans Control >50,000 >50,000 >50,000 >50,000 0.3% H2O2 02700 >50,000 >50,000 1% PG + 0.4% CAP + 0 0 0 0 0.3% H2O2

Only the 1% PG+0.4% CAP+0.3% H2O2 solution was able to completelydisinfect the catheter shafts following the transient contact with thedisinfecting solutions for all challenge organisms.

Data on Wound Ointment Containing GTN/CAP/PG:

Intrasite™ Gel ointment (Smith and Nephew, Andover, Mass.) consists of3% carboxymethylcellulose (CMC) and 20% propyleneglycol (PPG) and hasbeen used for many years in the treatment of chronic wounds (16). Theointment has shown benefit in maintaining hydration and in debridingchronic wounds. A wound healing clinical trial comparing honey toIntrasite™ Gel showed no significant differences in healing benefits(17). An antimicrobial wound ointment was prepared by mixing an aqueoussolution of 1% PG, 0.4% CAP, 0.03% GTN, 3% CMC and 20% PPG. This wasapplied as the disinfecting solution in the biofilm eradication modeldescribed above and tested against three recalcitrant bacterial woundcontaminants. Controls were the CMC-PPG ointment base and MEDIHONEY™ Thebioactive ointment showed rapid biofilm eradication for MRSA, PS, CA andCG (see Table below) with similar eradication times as for thePG+CAP+GTN combination. Time to biofilm eradication (in minutes) for theointment for additional wound pathogens is also reported in the Tablebelow:

TABLE 4 Carbapenem- resistant Vancomycin- (CRE) resistant StreptococcusEscherichia Enterococcus MRSA PS CA CG pyogenes coli (VRE)CMC-PPG >120 >120 >120 >120 >120 >120 >120 ointment baseMEDIHONEY ™ >120 15 >120 >120 >120 >120 >120 1% PG + 0.4% 60 15 30 15 1515 30 CAP + 0.03% GTN in CMC-PPG ointment

Clinical Trial Materials:

Antimicrobial wound ointment. The antimicrobial wound ointment (1%PG+0.4% CAP+0.03% GTN in CMC-PPG ointment base) may be clinically testedfor efficacy in healing contaminated wounds. For the proposed trial, theointment will be packaged for shipping and transport as anaqueous+non-aqueous, two component kit that can be mixed at the point ofuse. The aqueous component consists of a 0.04% sterile GTN intravenoussolution that can be shipped in the sterile containers received from themanufacturer (Baxter, Deerfield, Ill.). The non-aqueous componentconsists of: PG and CMC suspended in CAP+PPG liquids. The non-aqueoussuspension will be sterilized by gamma irradiation. The two sterileliquids can then be mixed at the point of use by simple exchange betweensyringes using a sterile luer connector (in approximately a 3:1 volumeratio) such that the final concentrations are 1% PG+0.4% CAP+0.03% GTNin 3% CMC-20% PPG ointment base. This antimicrobial ointment will beprepared and then shipped to the study sites for use.

Commercially available MEDIHONEY™: Honey is essentially asuper-saturated solution principally comprising of mixture of sugarstogether with small quantities of enzymes and amino acids, vitamins,mineral, organic acids, and aromatics responsible for its flavor andodor. MEDIHONEY™ is a standardized widely used medical honey. This honeyis sterilized by gamma irradiation to eliminate bacterial spores whichare known to be present in regular honey.

Clinical Trial Population:

The clinical study may be an open-label randomized trial between sisterinstitutions. Patients presenting with chronic wound including any ofthe following venous, arterial, diabetic, and pressure ulcers will berandomized to two equal groups: Group 1 will receive the antimicrobialwound ointment directly applied to wound beds and covered with asuitable dressing. Group 2 will receive the commercially availableMEDIHONEY™ ointment as the comparator.

Base line data collection will include gender, age, wound type, size(area and depth) and duration, ulcer location and history of recurrence,stage (I to IV for pressure ulcers), presence of necrosis, granulationand infection, medical history including deep venous thrombosis,hypertension, trauma or surgery to the affected limb, diabetes,immunosuppression and current medications. Patients will be assessed andmanaged in compliance with locally and nationally accepted guidelines.Reassessment of the wound should be undertaken at every dressing change,and documented at least once weekly or more frequent depending on woundpresentation using clinical judgment. Patients will be treated untilwound healing or for up to 12 weeks.

Wound Care

The usual proper debridement should be done if needed. Topical ointmentsconsisting of either the antimicrobial wound ointment for group 1 or theMEDIHONEY™ for group 2 will be used twice daily. VAC dressing could beapplied on wound with good granulation when applicable. All participantswill receive compression bandaging as standard background therapy.Dressing that maintains a moist wound healing environment will be used.A dressing that stays in place, minimizes shear and friction, and doesnot because additional tissue damage, will be recommended. Wounds mustbe swabbed if any signs of wound infection is evident by obtainingquantitative tissue biopsies and validated quantitative swab techniquesto provide objective evidence of control of the bacterial burden and tohelp qualify and speciate the offending pathogen. Pain must be assessedon a scale from 0 to 10 and evaluated and recorded weekly. Wound closureshould be assessed measured and recorded on healing charts that willrecord measurements of the wounds at weekly interval. Adverse eventshould be recorded if it is considered to be related to the studyagents. A full wound assessment should be done weekly and the rate ofwound healing should be evaluated at the end of the study therapy +/−7days.

Definitions

Chronic wounds are defined as wounds, which have failed to proceedthrough an orderly and timely reparative process to produce anatomic andfunctional integrity over a period of 3 months. Chronic wound are oftenidentified by the presence of a raised, hyperproliferative, yet noadvancing wound margin. Pressure ulcers are usually caused by thesustained application of surface pressure over a bony prominence, whichinhibits capillary blood flow to the skin and underlying tissue. If thepressure is not relieved it will normally ultimately result in celldeath followed by tissue necrosis and breakdown.

Leg or foot ulcers maybe venous, ischaemic, mixed aetiology or traumaticin origin. Infected wound is defined by the presence any of thefollowing: Cellulitis, abscess/pus, increased pain, increased exudate,malodour, delayed healing/deterioration, friable granulationtissue/bleeds easily, Evidence of tracking and temperature.

Patient's Eligibility

Inclusion criteria: Patients must meet the following criteria to beeligible for enrollment into the study: (1) Age>18 years old, (2) Canceror diabetic patients that had been diagnosed with any of the followingchronic wound categories: venous, arterial, diabetic, or pressureulcers, and (3) Capable of understanding the protocol and providinginformed consent.

Exclusion criteria: (1) Patients with allergy to Nitroglycerine,Pectinic acid, Caprilic acid, and MEDIHONEY™, (2) Pregnant women orlactating mother, and/or (3) Wound with osteomyelitis (stage IV pressureulcers).

Outcomes

The first aim of this trial is the efficacy in wound healing measured bythe improvement of wound closure at 6 and 12 weeks in addition to thequantitative microbiological evaluation of bacterial load on infectedwounds with the use of the novel antimicrobial wound ointment versusstandard of care wound treatment.

The second aim is to evaluate the safety and tolerability of the novelantimicrobial wound ointment as compared to the standard of careointment by assessing pain and the rates of study wound therapy relatedadverse events in both groups.

Clinical monitoring. The principle investigator of each collaboratingsister institution will be responsible for following the patients andcollecting all relevant clinical data including the adverse events thatare related to the study therapy.

Statistical Analysis and Sample Size

The aim 1 (efficacy) of the proposed study is to test the nullhypothesis that the population proportions of wound healing at 12 weeks,for the Honey treatment group and the antimicrobial wound ointmentgroup, are equal. To test this the inventors may conduct a 2-tailedbinary logistic regression analysis with the criterion for significance(alpha) set at 0.050 and that for the power (1-beta) set at 0.80. Therate of missing data could be assumed to be 10%. Our assumption aboutthe effect size is that the proportion with wound healed in the honeytreatment group at 12 week is 50% (cite previous study) and relativerisk estimate is 1.5. With these assumptions, our required sample sizeis 98 patients. The sample size calculations are based on “Sample sizeand optimal design for logistic regression with binary interaction”Demidenko, Statistics in Medicine, 27:36-46.

Our selection for chronic wounds is challenging. Those wounds areconsequences of underlying systemic diseases and therefore thesuccessful management of the underlying health problem may contribute tohealing to a greater extent than the type of dressing treatment used. Incontrast, cases where the underlying health problem may not be easilycontrolled such as refractory underlying immunosuppression, poorlycontrolled diabetes, or peripheral vascular diseases non amenable tovascular reconstruction, could result in decrease response to localwound therapy. However, we expect that with our randomization, cases ineach category will be equally distributed among both groups. Anotherpossible pitfall is that some patients may miss swab cultures or followup assessment. These patients will be included in an intent to treatanalysis. In addition, every effort will be made to assess all thepatients at end of therapy. In order to minimize this bias, a blindedinvestigator may perform the analysis of the measurement of the woundsize, which represents an objective outcome.

It is anticipated that this trial will provide a robust preliminarydata, and the trial may be followed by a multicenter, randomized,double-blind control trial comparing this antimicrobial ointment to thestandard of care. These therapeutic approaches may be used on high riskcancer and diabetic patients with devastating wound infections andcomplications. It is anticipated by the inventors that these approachesmay substantially improve wound healing in a clinical setting.

Example 3 Mammalian Cytotoxicity Testing of PG, CAP and PG+CAP Solutions

Mammalian cytotoxicity testing was conducting following the indirectmethod of de Gomes et al. (2011) where L929 mouse fibroblasts areexposed to extracts of challenge compositions over a concentration rangefrom 2% to 0.5% for 24 hours. (de Gomes et al., 2011). After exposureviability was tested using the Alamar Blue Assay (O'Brien et al., 2000)and the Trypan Blue Exclusuion assay (Strober W., 2015). L929Fibroblasts (ATCC #CCL-1; ATCC, Manassas, Va.) were maintained inDulbecco's-modified Eagle's medium (DMEM; Corning Cell Grow, Manassas,Va.) supplemented with 10% heat-inactivated fetal bovine serum (FBS;Sigma Aldrich, St. Louis, Mo.) in 5% CO2 at 37 C. Cells were seeded at adensity of 4.5×103 cells/well in 96 well culture plates for Alamar Blueassay and 2.8×105 cells in 25 cm2 culture flasks for live dead stainingFollowing the indirect exposure method of (de Gomes et al., 2011), whengrowth reached approximately 60% confluence cells were exposed to a 2%,1%, and 0.5% extracts of 1% PG+0.4% CAP in DMEM+10% FBS for 24 hours.Control, untreated cells were incubated in DMEM+10% FBS. After theexposures, cell viability and toxicity were assessed. All experimentswere performed in triplicate.

The Alamar Blue assay (Life Technologies, Corp., Carlsbad Calif.) wasused to assess the sensitivity of metabolic activity of fibroblastsfollowing exposure to PG+CAP. This assay measures the overall metabolicactivity based on reduction of resazurin to the highly fluorescentresorufin in response to reductive enzyme activity in cells. Cytotoxiccompounds cause fibroblasts to lose their ability to metabolicallyreduce resazurin to resorufin thus do not produce the fluorescentsignal. After 24 hr exposure to PG+CAP solutions, medium was replacedwith 100 uL of Hank's Balanced Salt Solution (HBSS; Corning Cell Grow,Manassas, Va.)+10% Alamar blue reagent and incubated for 4 hours in 5%CO2 at 37 C. Absorbance was determined at 570 nm using a microplatereader spectrophotometer. Cell viability (absorbance) was comparedbetween treated and untreated control cells. Control, untreated cellswere incubated in DMEM+10% FBS. All experiments were performed intriplicate. Results are expressed as a percentage of fluorescent signalnormalized to untreated controls.

The Trypan Blue exclusion test was used to determine the number ofviable cells present in cell suspension. Live cells with intactmembranes have the ability to exclude the dye Trypan Blue, whereas deadcells do not. Therefore viable cells had a clear cytoplasm whereas deadcells presented a blue cytoplasm. After 24 hr exposure to PG+CAP, cellswere washed with HBSS to remove any anti-trypsin serum proteins andharvested from the culture flask with 0.05% trypsin EDTA (Corning CellGrow, Manassas, Va.). Once detached, DMEM+10% FBS was added and cellswere pelleted at 200×g for 7 minutes. Supernatant was decanted and cellswere resuspended in 2 mL of HBSS. Aliquots of 10 uL cell suspension werestained with 10 uL 0.4% Trypan Blue (Sigma Aldrich, St. Louis, Mo.).Live and dead cells were counted with a hemacytometer. Control,untreated cells were incubated in DMEM+10% FBS. All experiments wereperformed in triplicate. Results were expressed as percent viable cellsin suspension.

Statistical analyses was conducted for comparisons of solutions using aStudent's T-test, two tailed, unequal variance. Alpha level was set at0.05 indicating a P-value<0.05 is significant. Results are shown in FIG.3.

In vitro cytotoxicity metabolic activity assay results are shown in FIG.3. L-929 Fibroblasts were treated with PG+CAP extracts for 24 hours.Cell metabolic activity was assessed with the Alamar Blue assay. Resultsare expressed as percentage metabolic activity relative to untreatedcontrol cells. There were no significant differences (p>0.31) inmetabolic activity between any of the groups compared to untreatedcontrol cells (by Student's t-test) indicating no appreciablecytotoxicity.

In vitro cytotoxicity cell viability assay results are shown in thetable below. L-929 Fibroblasts were treated with PG+CAP extracts for 24hours. Cell viability was assessed with the Trypan Blue exclusion assay.Results are expressed as percentage viable cells relative to untreatedcontrol cells. There was no significant difference (Student's t-test) incell viability between the groups (p=0.41) indicating no appreciablecytotoxicity.

TABLE 5 Cytotoxicity Cell Viability Assay Results Untreated L929Fibroblasts treated L929 Cells with 1% PG + 0.4% CAP (cells/mL)(cells/mL) Mean Live Cells ± 1.84 ± 0.18 × 10⁶ 1.57 ± 0.11 × 10⁶standard deviation Mean Dead Cells ± 6.00 ± 2.12 × 10⁴ 3.83 ± 0.60 × 10⁴standard deviation % Viable 96.89% 97.62%

Example 4 Assessment of Cytotoxicity of Polygalacturonic Acid+CaprylicAcid+Nitroglycerin Wound Ointment in a Mammalian Fibroblast Model

0.1% Polygalacturonic acid (PG)+0.4% Caprylic Acid (CAP)+0.03%Nitroglycerin (GTN) wound ointment has been shown in Example 3 to behighly effective in eradicating microbial biofilm. The previousexperiments demonstrated that PG+CAP is not cytotoxic in a mammalianfibroblast model. In this experiment the cytotoxicity of PG+CAP+GTN inan inert carboxymethylcellulose+propylene glycol ointment base wasassessed using a mammalian fibroblast (L929) model of Alamar Bluetesting and Trypan Exclusion assay.

Mouse fibroblast cell line, L929, was selected as it has been usedpreviously in mammalian cytotoxicity testing (Sousa de Gomes, et alCytotoxicity of denture adhesives. Clin Oral Invest. (2011) 15:885-893).Fibroblasts were maintained in Dulbecco's-modified Eagle's medium (DMEM)supplemented with 10% heat-inactivated fetal bovine serum (FBS) in 5%CO2 at 37 C. Cells were seeded at a density of 4.5×103 cells/well in 96well culture plates for Alamar Blue assay and 2.8×105 cells in 25 cm2culture flasks for live dead staining. When growth reached approximately60% confluence cells were exposed to a 2%, 1%, and 0.5% solution of the1% PG+0.4% CAP+0.03% GTN wound ointment in DMEM+10% FBS for 24 hours(denoted wound 2%, wound 1% and wound 0.5% in the plot below). DMEM+10%FBS was used for control, untreated cells. After exposure drug-inducedcell viability and toxicity were assessed with Alamar Blue and Trypanstaining for live/dead cell exclusion. All experiments were performed intriplicate.

The Alamar Blue assay (Life Technologies, Corp., Carlsbad Calif.) wasused to assess the sensitivity of fibroblasts to PG+CAP. This assaymeasured the overall metabolic activity of cells based on reduction ofresazurin to the highly fluorescent resorufin in response to reductiveenzyme activity in cells (2) Cells sensitive to the experimental drugrapidly lose their ability to metabolically reduce resazurin toresorufin thus do not produce the fluorescent signal. After 24 hrexposure to PG+CAP solutions, medium was replaced with 100 uL of Hank'sBalanced Salt Solution (HBSS)+10% Alamar blue reagent and incubated for4 hours in 5% CO2 at 37 C. Absorbance was determined at 570 nm using amicroplate reader spectrophotometer. Cell viability (absorbance) wascompared between treated and untreated control cells. Results expressedas a percentage of survival normalized to untreated controls.

Trypan blue exclusion test of cell viability is used to visuallydetermine the number of viable cells present in cell suspension. Livecells with intact membranes have the ability to exclude certain dyessuch as trypan blue, whereas dead cells do not. Cells in suspension arestained with 0.4% Trypan blue and counted on a hemacytometer. Viablecells will have a clear cytoplasm, dead cells will have a blue cytoplasm(3). After 24 hr exposure to wound ointment, cells were washed with HBSSto remove any anti-trypsin serum proteins and harvested from the cultureflask with 0.05% trypsin EDTA. Once detached, DMEM+10% FBS was added andcells were pelleted at 200×g for 7 minutes. Supernatant was decanted andcells were resuspended in 2 mL of HBSS. Aliquots of 10 uL cellsuspension was stained with 10 uL 0.4% trypan blue and live and deadcells were counted with a hemacytometer. Results are expressed aspercent viable cells in suspension.

Statistical analyses was conducted for comparisons of solutions using aStudent's T-test, two tailed, unequal variance. Alpha level was set at0.05 indicating a P-value<0.05 is significant.

No toxic effect from solutions of PG+CAP+GTN wound ointment weredetected with both the Alamar Blue assay and the Trypan Exclusion Test.The Figure below shows no significant difference between the metabolicactivity of cells exposed to solutions of PG+CAP+GTN wound ointmentcompared to cells grown in DMEM+10% FBS (p>0.09 for all solutionstested). Additionally, no significant difference was detected thepercent viability in fibroblasts exposed to PG+CAP+GTN wound ointmentcompared to untreated control cells (96.43% viable vs 96.8% viable,respectively; p=0.79; Table below)

TABLE 6 Cytotoxicity Results L929 Fibroblasts treated Untreated with 2%solution of 1% PG + L929 Cells 0.4% CAP + 300 ug/mL GTN (cells/mL)(cells/mL) Mean Live Cells ± 1.84 × 10⁶ ± 1.23 × 10⁶ ± standarddeviation 1.75 × 10⁵ 3.68 × 10⁴ Mean Dead Cells ± 6.0 × 10⁴ ± 4.60 × 10⁴± standard deviation 2.12 × 10⁴ 1.98 × 10⁴ % Viability 96.89% 96.43%

In vitro cytotoxicity assay results are shown in FIG. 4. L-929Fibroblasts were treated with PG+CAP+GTN Wound Ointment solutions for 24hours. Cell viability was assessed with the Alamar Blue assay. Resultsare expressed as percentage viable cells relative to control untreatedcells.

All of the methods disclosed and claimed herein can be made and executedwithout undue experimentation in light of the present disclosure. Whilethe compositions and methods of this invention have been described interms of preferred embodiments, it will be apparent to those of skill inthe art that variations may be applied to the methods and in the stepsor in the sequence of steps of the method described herein withoutdeparting from the concept, spirit and scope of the invention. Morespecifically, it will be apparent that certain agents which are bothchemically and physiologically related may be substituted for the agentsdescribed herein while the same or similar results would be achieved.All such similar substitutes and modifications apparent to those skilledin the art are deemed to be within the spirit, scope and concept of theinvention as defined by the appended claims.

REFERENCES

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

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1-101. (canceled)
 102. A catheter comprising: a first end and a secondend; a central lumen extending from the first end and the second end; acatheter wall disposed around the central lumen, wherein the catheterwall comprises an outer surface; a first reservoir and a secondreservoir; a first conduit in fluid communication with the firstreservoir; a second conduit in fluid communication with the secondreservoir; and a plurality of outlet ports in in the first reservoir.103. The catheter of claim 102 further comprising: (i) a first inletport in fluid communication with the first conduit; and (ii) a secondinlet port in fluid communication with the second conduit; wherein thefirst conduit and the second conduit are in located within the catheterwall.
 104. (canceled)
 105. The catheter of claim 102 wherein theplurality of outlet ports are arranged circumferentially around theouter surface of the catheter wall.
 106. The catheter of claim 102further comprising a first valve configured to control flow in the firstconduit; and further comprising a second valve configured to controlflow in the second conduit.
 107. (canceled)
 108. The catheter of claim102 further comprising an irrigation fluid container in fluidcommunication with the first conduit.
 109. The catheter of claim 108wherein the irrigation fluid container is a first syringe.
 110. Thecatheter of claim 108 wherein the irrigation fluid container is coupledto a pump.
 111. The catheter of claim 108 wherein the irrigation fluidcontainer comprises an antimicrobial composition.
 112. The catheter ofclaim 108 wherein the irrigation fluid container is configured to directirrigation fluid through the first conduit and the plurality of outletports in the first reservoir.
 113. The catheter of claim 102 furthercomprising a first inlet port in fluid communication with the firstconduit, wherein the first inlet port is proximal to the first end. 114.The catheter of claim 113 further comprising an irrigation fluidcontainer configured to direct irrigation fluid through the first inletport, the first conduit and the plurality of outlet ports in the firstreservoir.
 115. The catheter of claim 102 further comprising a pressuresource in fluid communication with the second conduit; wherein thepressure source is a second syringe, and wherein the pressure source isconfigured to inflate the second reservoir via the second conduit.116-117. (canceled)
 118. The catheter of claim 115 further comprising asecond inlet port in fluid communication with the second conduit,wherein the second inlet port is proximal to the second end; and whereinthe pressure source is configured to inflate the second reservoir viathe second inlet port and the second conduit.
 119. (canceled)
 120. Thecatheter of claim 102, wherein the catheter comprises an antimicrobialcomposition comprising: from about 0.5% to about 3% (w/w) of apolygalacturonic acid mixture and from greater than 0.1% to about 5%(w/w) of a C₆₋₁₂ fatty acid; wherein the ratio of the polygalacturonicacid mixture consists of esterified polygalacturonic acid andde-esterified polygalacturonic acid in an amount of at least about 50%de-esterified polygalacturonic acid; wherein the C₆₋₁₂ fatty acid ishexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, caprylicacid (octanoic acid), caproic acid, or lauric acid.
 121. The catheter ofclaim 120, wherein the C₆₋₁₂ fatty acid is caprylic acid (octanoicacid).
 122. The catheter of claim 120, wherein the fatty acid isprotonated or a free acid.
 123. The catheter of claim 120, wherein theantimicrobial composition has a pH of about 3.7-4.8.
 124. The catheterof claim 120, wherein said amount is at least about 70% de-esterifiedpolygalacturonic acid, wherein the de-esterified polygalacturonic acidis substantially deprotonated.
 125. The catheter of claim 120, whereinthe antimicrobial composition further comprises hydrogen peroxide. 126.The catheter of claim 125, wherein the hydrogen peroxide is present inthe antimicrobial composition in an amount of from about 0.1% to about3%.
 127. The catheter of claim 120, wherein the antimicrobialcomposition further comprises one or more additional antimicrobialagent, wherein the one or more additional antimicrobial agent is anantibiotic, an antiseptic, chlorhexidine, gendine, gardine, silver,nanosilver, silver sulfadiazine, polyhexamethylene biguanide (PHMB), achelator, ethanol, a nitric oxide donor, a quarternary ammoniumantimicrobial, or mixtures thereof.
 128. The catheter of claim 127,wherein the antimicrobial composition comprises the nitric oxide donor,and wherein the nitric oxide donor is a glyceryl nitrate, nitroprusside,nitrosoglutathione, a nitroso compound, nitrosothiol, nitrosocystein,nitrosoalbumin, nitro compounds, nitroaspiririn, isosorbide,diazeniumdiolate, nitrate, or nitrite.
 129. The catheter of claim 128,wherein the glyceryl nitrate is glyceryl trinitrate (GTN), and whereinthe antimicrobial composition comprises about 0.01-1% glyceryltrinitrate (GTN).
 130. The catheter of claim 127, wherein the antibioticis minocycline, rifampin, an aminoglycoside, quinolone, carbapenem,cephalosporin, glycopeptide, lipopeptide, lincosamide, macrolide,monobactam, nitrofuran, oxazolidinone, penicilin, polypeptide,sulfonamide, tetracycline, metronidazole, muciprocin, anti-mycobacterialcompound, or chloramphenicol.
 131. The catheter of claim 127, whereinthe chelator is mercaptoethane sulfonate (MeSNA), citrate, EDTA, EDDS,or N-acetyl cysteine.
 132. The catheter of claim 120, wherein theantimicrobial composition further comprises an analgesic agent, anantiscarring agent, an anti-inflammatory agent, an anticoagulant,glycerol, a silicone compound, a vitamin, humectant, a polymer, alubricant, a tactile agent, a thickener, a gelling agent, an emollient,a surfactant, an emulsifier, a moisturizer, a coloring or tinting agent,or a fragrance.
 133. The catheter of claim 120, wherein the solutioncomprises a pharmaceutically acceptable saline diluent.
 134. Thecatheter of claim 120, wherein the antimicrobial composition comprises aprotein, wherein the protein is gelatin, a plasticized gelatin, analginate, a chitosan, collagen, or a proteoglycan.
 135. The catheter ofclaim 134, wherein the antimicrobial composition comprises about 1-5%carboxymethyl cellulose and about 10-30% propylene glycol.
 136. Thecatheter of claim 120, wherein the antimicrobial composition comprisesabout 0.5-2% pectinic acid, about 0.3-0.5% caprylic acid, and about0.01-1% glyceryl trinitrate (GTN).
 137. The catheter of claim 120,wherein the antimicrobial composition comprises about 1-1000micrograms/ml glyceryl trinitrate and about 0.1-1% hydrogen peroxide.138. A method of disinfecting or cleaning a catheter in a subject,comprising administering an antimicrobial composition to the subject viathe catheter of claim
 102. 139. The method of claim 138, wherein thesubject is a human.
 140. The method of claim 138, wherein theantimicrobial composition is administered to the urethra of the subject.141. The method of claim 138, wherein the antimicrobial composition isadministered to treat a stricture in the subject.
 142. The method ofclaim 140, wherein the subject has a chronic wound.
 143. The method ofclaim 138, wherein the catheter is further defined as a long-termcatheter.
 144. The method of claim 143, wherein the long-term catheteris a long term tunneled central venous catheter or a long term urinarycatheter.
 145. The method of claim 138, wherein the catheter is used todeliver a medicated fluid or a lubricious fluid to an outer surface ofthe catheter.
 146. The method of claim 145, wherein the medicated fluidcomprises a pain reliever, antifibrotic agent, mucolytic medication,collagenolytic agent.
 147. The method of claim 145, wherein themedicated fluid or the lubricious fluid comprises a fragrance.
 148. Themethod of claim 138, wherein the antimicrobial composition comprises oneor more aromatic, lubricious, moisturizing, pain relief, oranti-inflammatory additive.